Inhibitors of activin receptor-like kinase

ABSTRACT

Described herein are compounds that inhibit ALK2 and its mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.

CLAIM OF PRIORITY

This application claims priority from U.S. Ser. No. 62/332,948, filedApr. 15, 2016, and U.S. Ser. No. 62/411,172, filed Oct. 21, 2016, eachof which is incorporated herein in its entirety.

This disclosure relates to inhibitors of Activin receptor-like kinase-2(ALK2).

BACKGROUND

Activin receptor-like kinase-2 (ALK2) is encoded by the Activin Areceptor, type I gene (ACVR1). ALK2 is a serine/threonine kinase in thebone morphogenetic protein (BMP) pathway (Shore et al., Nature Genetics2006, 38: 525-27). It binds to complexes comprising bone morphogeneticproteins (BMPs) and is responsible for transducing BMP signals. Certainmutations in ALK2 cause the kinase to be constitutively active and areassociated with various diseases. Fibrodysplasia ossificans progressiva(FOP) is a rare, severely debilitating heritable disorder characterizedby progressive heterotopic ossification in extraskeletal sites.Individuals with this disease experience significantly reduced mobilityand shortened lifespan. Current therapy is limited to amelioratingswellings (flare-ups) that characterize the disease.

All FOP patients carry heterozygous, activating mutations in the ACVR1gene. Further, the vast majority of FOP patients harbor the same ALK2mutation, R206H. Transgenic mice that express ALK2-R206H recapitulatethe key features of the human disease, including malformation of thefirst digit in the hind limbs and inflammatory infiltration and musclecell apoptosis followed by formation of heterotopic bone through anendochondral pathway (Chakkalakal et al., J Bone Miner Res. 2012, 27(8):1746-1756). A second engineered mouse strain has been developed thatexpresses the activated ALK2-Q207D variant in muscle and phenocopies keyfeatures of human FOP. Treatment of these mice with an inhibitor of BMPreceptor type 1 kinases resulted in inhibition of SMAD signaling andreduction in ectopic ossification and associated functional impairment(Fukuda et al., Genesis 2006, 44, 159-167). Other mutations in ALK2 thathave been associated with FOP include but are not limited to L196P,PF197-8L, R202I, R258S, R258G, G328A, G328W, G328E, G328R, G356D, andR375P (Kaplan et al., Hum Mutat. 2009, 30(3): 379-390; Gregson et al.,Bone 2011, 48:654-658; Kaplan et al., Am J Med Genet 2015, 167:2265-2271; Petrie et al., PLoS One 2009, 4(3): e5005; Bocciardi et al.,Eur J Hum Genetics 2009, 17:311-318; Pacifici and Shore, Cytokine &Growth Factor Reviews 2016, 27:93-104).

In certain circumstances, heterotopic ossification (HO) can also beinduced in people who are wild-type ALK2. These circumstances caninclude major surgical interventions, trauma (such as head or blastinjuries), protracted immobilization, or severe burns. An ALK2 inhibitorcould potentially be an effective therapy for the treatment of FOP andother conditions caused by HO.

Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive andtypically fatal pediatric brain stem cancer with no effective treatmentoptions. Due to its anatomical location and diffuse nature, DIPG cannotbe treated by surgery. DIPG arises exclusively in young children and thetwo year survival rate is approximately less than 10%. Because of theirlocation in the brainstem, DIPGs cause pressure on cranial nervesleading to double vision, difficulty in controlling eye movement,difficulty chewing/swallowing, weakness in the arms/legs leading to lossof movement and difficulty speaking. As the tumor progresses there isincreasing pressure inside the skull causing severe headaches,nausea/vomiting and fatigue. Unlike many other pediatric cancers, therehas been virtually no progress in improving treatments for DIPG over thelast few decades. Historically, the lack of understanding regarding thedrivers of DIPG has hindered the identification of potential newtreatment options. Consequently, the medical need for DIPG treatments isexceedingly high. Recent genomic characterization has demonstrated that˜25% of DIPG tumors possess somatic, heterozygous ALK2 activatingmutations. Mutations in ALK2 associated with DIPG include, but are notlimited to R206H, G328V, G328W, G328E, and G356D (Jones and Baker,Nature Rev Cancer 2014, 14:651-661).

Notably, the ALK2 mutations found in DIPG overlap with those found inFOP, suggesting a potential synergy between inhibitor developmentefforts for the two diseases (e.g., via overlapping screening funnelsand chemistry efforts). The finding that a significant proportion ofDIPG contain activating ALK2 mutations suggests that ALK2 inhibitors maybe of clinical benefit for DIPG patients.

Anemia of chronic disease, inflammation or cancer can develop insettings of chronic inflammatory, infectious, or neoplastic disease. Inthis form of anemia, inflammatory cytokines, induce hepatic expressionof hepcidin, which negatively regulates iron bioavailability byinactivating ferroportin. Hepcidin is transcriptionally regulated byamongst other things bone morphogenetic protein (BMP) signaling.Inhibition of BMP phosphorylation through inhibition of ALK2 canmodulate BMP-mediated signaling, thus reducing hepcidin expression.Reduced hepcidin expression may be an effective strategy for thetreatment of anemia of chronic disease, inflammation, or cancer.

SUMMARY

The present disclosure provides inhibitors of ALK2 and ALK2 mutants,e.g., ALK2 mutants as defined herein, for example, inhibitors ofstructural formula (I) and formula (Ia) and pharmaceutically acceptablesalts and compositions thereof. The present disclosure further providesmethods of using the compounds of the disclosure, and pharmaceuticallyacceptable salts and compositions thereof, to inhibit the activity ofALK2 or ALK2 mutants in a cell or in a patient. The present disclosurefurther provides methods for using the compounds of the disclosure andpharmaceutically acceptable salts and compositions thereof, to treat asubject or patient suffering from a condition mediated by aberrant ALK2activity, e.g., at least one of fibrodysplasia ossificans progressiva(FOP) or heterotopic ossification or diffuse intrinsic pontine glioma(DIPG) or anemia of chronic disease or anemia of inflammation or anemiaof cancer.

In one aspect, the disclosure features a compound of structural formula(I) or at least one of pharmaceutically acceptable salt thereof:

wherein each of ring A, R¹, R², R³, and n is defined as describedherein.

In another aspect, the present disclosure provides pharmaceuticalcompositions comprising a compound of structural formula (I) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

In another aspect, the present disclosure provides a method for treatingor ameliorating fibrodysplasia ossificans progressiva in a subject. Inan embodiment, said method comprises administering to the subject atherapeutically effective amount of a compound of structural formula (I)or a pharmaceutically acceptable salt or composition thereof. In anembodiment, the subject has a mutation in an ALK2 gene that results inthe expression of an ALK2 enzyme having an amino acid modificationselected from one or more of L196P, PF197-8L, R202I, R206H, Q207E,R258S, R258G, G328A, G328W, G328E, G328R, G356D, and R375P.

In another aspect, the present disclosure provides a method of treatingor ameliorating diffuse intrinsic pontine glioma in a subject. In anembodiment, said method comprises administering to the subject atherapeutically effective amount of a compound of structural formula (I)or a pharmaceutically acceptable salt or composition thereof. In anembodiment, the subject has a mutation in an ALK2 gene that results inthe expression of an ALK2 enzyme having an amino acid modificationselected from one or more of R206H, G328V, G328W, G328E, and G356D.

In another aspect, the present disclosure provides a method ofinhibiting aberrant ALK2 activity in a subject. In an embodiment, saidmethod comprises administering to the subject a therapeuticallyeffective amount of a compound of structural formula (I) or apharmaceutically acceptable salt or composition thereof. In anembodiment, the subject has a mutation in an ALK2 gene that results inthe expression of an ALK2 enzyme having an amino acid modificationselected from one or more of L196P, PF197-8L, R202I, R206H, Q207E,R258S, R258G, G328A, G328V, G328W, G328E, G328R, G356D, and R375P.

The methods described herein can additionally comprise variousevaluation steps prior to, during, and/or following treatment with acompound of the disclosure. In an embodiment, prior to, during and/orfollowing treatment with a compound of the disclosure, the methodfurther comprises the step of evaluating, e.g., visualizing, heterotopicossification in the subject. This may be achieved by spectroscopicanalysis, e.g., magnetic resonance-based analysis, e.g., MRI, positronemission tomography (PET), micro computed tomography (μCT), or byhistology.

In an embodiment, the methods comprise evaluating a pre-treatment orbaseline level of the heterotopic ossification in a subject, e.g., usingspectroscopic analysis, e.g., magnetic resonance-based analysis, e.g.,MRI, positron emission tomography (PET), micro computed tomography(μCT), or by histology. In an embodiment, the methods further compriseadministering to the subject a compound of the disclosure; evaluatingthe post-treatment level of heterotopic ossification, e.g., usingspectroscopic analysis, e.g., magnetic resonance-based analysis, e.g.,MRI, positron emission tomography (PET), micro computed tomography(μCT), or by histology; comparing the post-treatment level ofheterotopic ossification in the subject with the pre-treatment orbaseline level of heterotopic ossification; and determining whether tocontinue treatment, e.g., using spectroscopic analysis, e.g., magneticresonance-based analysis, e.g., MRI, positron emission tomography (PET),micro computed tomography (μCT), or by histology.

In an embodiment, the heterotopic ossification is preceded by edema,e.g., sustained edema.

Embodiments of the Disclosure Definitions

As used herein, the terms a “patient,” “subject,” “individual,” and“host” refer to either a human or a non-human animal suffering from orsuspected of suffering from a disease or disorder associated withaberrant ALK2 activity (i.e., aberrant ALK2 activity due to a mutationin an ALK2 gene that results in the expression of an ALK2 enzyme havingan amino acid modification) or aberrant ALK2 biological activity.

“Treat”, “treatment” and “treating” such a disease or disorder refers toameliorating at least one symptom of the disease or disorder describedherein. These terms, when used in connection with a condition such asfibrodysplasia ossificans progressiva, refer to one or more of:controlling the rate of heterotropic bone growth; relieving pain andinflammation associated with development of new bone; extending theexpected survival time of the patient; reducing the size or the numberof heterotopic bone growth lesions; maintaining or improving mobility;preventing or treating new flare ups; inhibiting the development of newheterotopic bone lesions; enabling surgery to remove existingheterotopic ossifications to restore limb function and/or mobility;prolonging survival; prolonging progression-free survival; prolongingtime to progression; inhibiting FOP related injury induced edema, and/orenhancing quality of life. When used in connection with a condition suchas diffuse intrinsic pontine glioma, these terms refer to one or moreof: impeding growth of the glioma, causing the glioma to shrink byweight or volume, extending the expected survival time of the patient,inhibiting glial tissue growth, reducing glial tumor mass, reducing sizeor number of metastatic lesions, inhibiting the development of newmetastatic lesions, prolonging survival, prolonging progression-freesurvival, prolonging time to progression, and/or enhancing quality oflife.

The term “therapeutic effect” refers to a beneficial local or systemiceffect in animals, particularly mammals, and more particularly humans,caused by administration of a compound or composition of the disclosure.The phrase “therapeutically effective amount” means that amount of acompound or composition of the disclosure that is effective to treat adisease or condition associated with aberrant ALK2 activity at areasonable benefit/risk ratio. The therapeutically effective amount ofsuch substance will vary, for example, depending upon the subject anddisease condition being treated, the weight and age of the subject, theseverity of the disease condition, the manner of administration, etc.,which can readily be determined by one of skill in the art.

“Alkylene” refers to a divalent radical of an alkyl group, e.g., —CH₂—,—CH₂CH₂—, and —CH₂CH₂CH₂—.

“Alkyl” or “alkyl group” refers to a monovalent radical of a saturatedstraight or branched hydrocarbon, such as a straight or branched groupof 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂ alkyl,C₁-C₁₀ alkyl, and C₁-C₆ alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

“Aromatic” when referring to a ring is art-recognized, and refers to afully conjugated, unsaturated ring that has 4n+2π electrons and is oftencharacterized by structural formulae showing alternating double andsingle bonds. Aromatic rings include both benzene and rings containingone or more heteroatoms selected from N, O and S.

“Aryl” refers to a ring system is art-recognized and refers to amonocyclic, bicyclic or polycyclic hydrocarbon ring system wherein atleast one ring is aromatic.

“Halo” refers to a radical of any halogen, e.g., —F, —Cl, —Br, or —I.

“Carbocyclic ring system” refers to a monocyclic, bicyclic or polycyclichydrocarbon ring system, wherein each ring is either completelysaturated or contains one or more units of unsaturation, but where noring is aromatic.

“Carbocyclyl” refers to a monovalent radical of a carbocyclic ringsystem. Representative carbocyclyl groups include cycloalkyl groups(e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like),and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl,cyclopentadienyl, and the like).

“Cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or polycyclicnon-aromatic hydrocarbon groups having 3 to 12 carbons. Anysubstitutable ring atom may be substituted (e.g., by one or moresubstituents). The cycloalkyl groups can contain fused or spiro rings.Fused rings are rings that share at least two common (carbon) atoms.Examples of cycloalkyl moieties include, but are not limited to,cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

“Heteroalkyl” refers to a monovalent, straight or branched alkyl chainwhere one methylene unit other than the methylene unit bound to the restof the molecule is replaced with —O—, —S—, or —N(R^(d)), wherein R^(d)is defined below. For the sake of clarity, the moiety —CH₂—NH—CH₃ wouldbe a heteroalkyl, but —NH—CH₂—CH₃ would not because the —NH group isbound to the rest of the molecule.

“Heteroalkylene” refers to a divalent radical of a heteroalkyl group.

“Heteroaromatic ring system” is art-recognized and refers to amonocyclic, bicyclic or polycyclic ring system wherein at least one ringis both aromatic and comprises at least one heteroatom (e.g., N, O, orS); and wherein no other rings are heterocyclyl (as defined below). Incertain instances, a ring which is aromatic and comprises a heteroatomcontains 1, 2, 3, or 4 ring heteroatoms in such ring.

“Heteroaryl” refers to a monovalent radical of a heteroaromatic ringsystem. Representative heteroaryl groups include ring systems where (i)each ring comprises a heteroatom and is aromatic, e.g., imidazolyl,oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl,pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl; (ii) each ring is aromatic orcarbocyclyl, at least one aromatic ring comprises a heteroatom and atleast one other ring is a hydrocarbon ring or e.g., indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, pyrido[2,3-b]-1,4-oxazin-3-(4H)-one,5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl; and(iii) each ring is aromatic or carbocyclyl, and at least one aromaticring shares a bridgehead heteroatom with another aromatic ring, e.g.,4H-quinolizinyl.

“Heterocyclic ring system” refers to monocyclic, bicyclic and polycyclicring systems where at least one ring is saturated or partiallyunsaturated (but not aromatic) and that ring comprises at least oneheteroatom. A heterocyclic ring system can be attached to its pendantgroup at any heteroatom or carbon atom that results in a stablestructure and any of the ring atoms can be optionally substituted.Heterocyclic ring systems may be fused rings.

“Heterocyclyl” refers to a monovalent radical of a heterocyclic ringsystem. Representative heterocyclyls include ring systems in which (i)every ring is non-aromatic and at least one ring comprises a heteroatom,e.g., tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl,pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl;(ii) at least one ring is non-aromatic and comprises a heteroatom and atleast one other ring is an aromatic carbon ring, e.g.,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (iii)at least one ring is non-aromatic and comprises a heteroatom and atleast one other ring is aromatic and comprises a heteroatom, e.g.,3,4-dihydro-1H-pyrano[4,3-c]pyridine, and1,2,3,4-tetrahydro-2,6-naphthyridine.

“Cyano” refers to a —CN radical.

“Hydroxy” or “hydroxyl” refers to —OH.

Certain compounds of the present disclosure may exist in particulargeometric or stereoisomeric forms. The present disclosure contemplatesall such compounds, including cis- and trans-isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the disclosure. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in thisdisclosure. Thus, when a disclosed compound is named or depicted by astructure without specifying the stereochemistry and has one or morechiral centers, it is understood to represent all possible stereoisomersof the compound, as well as enantiomeric mixtures thereof. When adisclosed compound is named or depicted by a structure specifyingstereochemistry at each chiral center, it is understood to representonly the compound having the designated stereochemistry at such chiralcenters. However, when a disclosed compound specifies stereochemistry atsome, but not all chiral centers, it is understood to represent allpossible stereoisomers at the non-specified chiral centers of thecompound, as well as enantiomeric mixtures thereof.

If, for instance, a particular enantiomer of compound of the presentdisclosure is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.

ee=(90-10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%.

The compounds or compositions described herein may contain anenantiomeric excess of at least 50%, 75%, 90%, 95%, or 99% of one formof the compound, e.g., the S-enantiomer. In other words such compoundsor compositions contain an enantiomeric excess of the S enantiomer overthe R enantiomer.

The compounds described herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example deuterium (²H), tritium (³H),carbon-13 (¹³C), or carbon-14 (¹⁴C). All isotopic variations of thecompounds disclosed herein, whether radioactive or not, are intended tobe encompassed within the scope of the present disclosure. In addition,all tautomeric forms of the compounds described herein are intended tobe within the scope of the claimed disclosure.

The compound can be useful as the free base or as a salt. Representativesalts include the hydrobromide, hydrochloride, sulfate, bisulfate,phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate,laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthalate, mesylate, glucoheptonate,lactobionate, and laurylsulfonate salts and the like. (See, for example,Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.)

As described herein, compounds of the disclosure may contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at eachposition. Combinations of substituents envisioned under this disclosureare preferably those that result in the formation of stable orchemically feasible compounds. The term “stable”, as used herein, refersto compounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable substituents for an optionally substituted alkyl, alkylene,carbocyclyl, heterocyclyl, aryl group and heteroaryl group includehalogen,

-   ═O, —CN, —OR^(c), —NR^(d)R^(e), —S(O)_(k)R^(c), —NR^(c)S(O)₂R^(c),    —S(O)₂NR^(d)R^(e), —C(═O)OR^(c), —OC(═O)OR^(c), —OC(═O)R^(c),    —OC(═S)OR^(c), —C(═S)OR^(c), —O(C═S)R^(c), —C(═O)NR^(d)R^(e),    —NR^(c)C(═O)R^(c), —C(═S)NR^(d)R^(e), —NR^(c)C(═S)R^(c),    —NR^(c)(C═O)OR^(c), —O(C═O)NR^(d)R^(e), —NR^(c)(C═S)OR^(c),    —O(C═S)NR^(d)R^(e), —NR^(c)(C═O)NR^(d)R^(e),    —NR^(c)(C═S)NR^(d)R^(e), —C(═S)R^(c), —C(═O)R^(c), C₁-C₆ alkyl,    C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, carbocyclyl,    (C₁-C₆-alkylene)-carbocyclyl, (C₁-C₆-heteroalkylene)-carbocyclyl,    heterocyclyl, (C₁-C₆-alkylene)-heterocyclyl,    (C₁-C₆-heteroalkylene)-heterocyclyl, aryl, (C₁-C₆-alkylene)-aryl,    (C₁-C₆-heteroalkylene)-aryl, heteroaryl,    (C₁-C₆-alkylene)-heteroaryl, or (C₁-C₆-heteroalkylene)-heteroaryl,    wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene,    carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally    substituted with one or more of halogen,-   OR^(c), —NO₂, —CN, —NR^(c)C(═O)R^(c), —NR^(d)R^(e), —S(O)_(k)R^(c),    —C(═O)OR^(c), —C(═O)NR^(d)R^(e), —C(═O)R^(c), C₁-C₆ alkyl, C₁-C₆    haloalkyl, or C₁-C₆ heteroalkyl, and wherein R^(c) is hydrogen,    hydroxy, C₁-C₆ alkyl, C1-C₆ heteroalkyl, carbocyclyl,    (C₁-C₆-alkylene)-carbocyclyl, (C₁-C₆-heteroalkylene)-carbocyclyl,    heterocyclyl, (C₁-C₆-alkylene)-heterocyclyl,    (C₁-C₆-heteroalkylene)-heterocyclyl, aryl, (C₁-C₆-alkylene)-aryl,    (C₁-C₆-heteroalkylene)-aryl, heteroaryl,    (C₁-C₆-alkylene)-heteroaryl, or (C₁-C₆-heteroalkylene)-heteroaryl,    each of which is optionally substituted with one or more of halogen,    hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl,    carbocyclyl, heterocyclyl, aryl, or heteroaryl; R^(d) and R^(e) are    each independently selected from hydrogen, C₁-C₆ alkyl, or C₁-C₆    heteroalkyl; and k is 0, 1, or 2. The claimed disclosure is not    intended to be limited in any manner by the above exemplary listing    of substituents.

Compounds

In one aspect, the present disclosure features a compound having thestructural formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is phenyl or heteroaryl, wherein ring A is substituted        with 0, 1, 2, or 3 independently selected substituents in        addition to R²;    -   R¹ is selected from NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆        alkyl, —O—C₁-C₆ alkyl, —C(O)—C₁-C₄ alkyl, carbocyclyl,        heterocyclyl, —O—(C₀-C₄ alkylene)-carbocyclyl, —O—(C₀-C₄        alkylene)-heterocyclyl, —NH—(C₀-C₄ alkylene)-carbocyclyl, and        —NH—(C₀-C₄ alkylene)-heterocyclyl, wherein each alkyl, alkylene,        carbocyclyl, and heterocyclyl portion of R¹ is unsubstituted or        is independently substituted with 1, 2, 3, or 4 independently        selected substituents; or    -   R¹ is taken together with one R³ to form a saturated ring fused        to the piperazine ring in formula (I), and wherein the ring        formed by R¹ and R³ is unsubstituted, or is substituted with 1,        2, or 3 independently selected substituents;    -   R² is selected from halo, C₁-C₆ alkyl, heterocyclyl, cycloalkyl,        —NH—(C₀-C₄ alkylene)-heterocyclyl, —(C₁-C₄        alkylene)-heterocyclyl, and —O—(C₀-C₄ alkylene)-heterocyclyl,        wherein any heterocyclyl, cycloalkyl, alkyl, or alkylene portion        of R² is unsubstituted or is substituted with 1, 2, 3, or 4        independently selected substituents; or    -   R² is taken together with any ring atom in ring A to form a        cycloalkyl or saturated heterocyclyl ring that is fused,        spirofused, or bridged to ring A, and wherein the ring formed by        R² and the ring atom in ring A is unsubstituted, or is        substituted with 1, 2, or 3 independently selected substituents;    -   each R³, if present, is independently selected from C₁-C₄ alkyl        and C₁-C₄ haloalkyl; and    -   n is 0, 1, 2, or 3.

In certain embodiments of Formula I, R¹ may additionally be selectedfrom —NH-aryl, —NH—O—(C₁-C₄ alkyl), and —S-heterocyclyl.

In certain embodiments of Formula I, R² may additionally be selectedfrom —(C₁-C₄ alkylene)-NH-heterocyclyl.

In an embodiment, the compound is a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein:

-   -   ring A is phenyl or heteroaryl, wherein ring A is substituted        with 0, 1, 2, or 3 independently selected substituents in        addition to R²;    -   R¹ is selected from NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆        alkyl, —O—C₁-C₆ alkyl, —C(O)—C₁-C₄ alkyl, carbocyclyl,        heterocyclyl, —O—(C₀-C₄ alkylene)-carbocyclyl, —O—(C₀-C₄        alkylene)-heterocyclyl, —NH—(C₀-C₄ alkylene)-carbocyclyl, and        —NH—(C₀-C₄ alkylene)-heterocyclyl, wherein each alkyl, alkylene,        carbocyclyl, and heterocyclyl portion of R¹ is unsubstituted or        is independently substituted with 1, 2, 3, or 4 independently        selected substituents; or    -   R¹ is taken together with one R³ to form a saturated ring fused        to the piperazine ring in formula (I), and wherein the ring        formed by R¹ and R³ is unsubstituted, or is substituted with 1,        2, or 3 independently selected substituents;    -   R² is selected from halo, C₁-C₆ alkyl, heterocyclyl, cycloalkyl,        —NH—(C₀-C₄ alkylene)-heterocyclyl, and —O—(C₀-C₄        alkylene)-heterocyclyl, wherein any heterocyclyl, cycloalkyl,        alkyl, or alkylene portion of R² is unsubstituted or is        substituted with 1, 2, 3, or 4 independently selected        substituents; or    -   R² is taken together with any ring atom in ring A to form a        cycloalkyl or saturated heterocyclyl ring that is fused,        spirofused, or bridged to ring A, and wherein the ring formed by        R² and the ring atom in ring A is unsubstituted, or is        substituted with 1, 2, or 3 independently selected substituents;    -   each R³, if present, is independently selected from C₁-C₄ alkyl        and C₁-C₄ haloalkyl; and    -   n is 0, 1, 2, or 3.

In an embodiment, n is 0 or 1; and R³, if present, is selected frommethyl, ethyl, and —CHF₂.

In an embodiment, ring A is selected from:

wherein:

-   -   “1” represents a portion of ring A bound to a        pyrrolo[1,2-b]pyridazine moiety;    -   “2” represents a portion of ring A bound to R²; and    -   ring A is substituted with 0, 1, 2, or 3 independently selected        substituents in addition to R².

In an embodiment, ring A is selected from:

wherein:

-   -   “1” represents a portion of ring A bound to a        pyrrolo[1,2-b]pyridazine moiety;    -   “2” represents a portion of ring A bound to R²; and    -   ring A is substituted with 0, 1, 2, or 3 independently selected        substituents in addition to R².

In an embodiment, ring A is selected from phenyl and pyridinyl. In oneaspect of this embodiment, ring A is selected from phenyl andpyridin-2-yl.

In an embodiment, ring A is substituted with 0, 1, or 2 substituents inaddition to R², wherein each of the substituents is independentlyselected from halo, methyl, and —OCHF₂.

In an embodiment, ring A is substituted with 0, 1, or 2 substituents inaddition to R², wherein each of the substituents is independentlyselected from halo, methyl, —CN, and —OCHF₂.

In an embodiment, R¹ is selected from —C(O)—(C₁-C₃ alkyl), C₁-C₃ alkyl,—O—(C₁-C₅ alkyl), —NH(C₁-C₅ alkyl), —N(C₁-C₄ alkyl)₂, —NH—(C₃-C₆cycloalkyl), C₃-C₆ cycloalkyl, —O—(C₃-C₆ cycloalkyl), —O—(C₁-C₃alkyl)-(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl),—O—(C₀-C₃ alkylene)-(O-containing heterocyclyl), —NH—(C₀-C₃alkylene)-(O-containing heterocyclyl), an O-containing heterocyclyl, andan N-containing heterocyclyl, wherein any alkyl, alkylene, cycloalkyl,or heterocyclyl portion of R¹ is unsubstituted, or is substituted with1, 2, or 3 substituents independently selected from halo, cyano, acetyl,C₁-C₄ alkyl, C₁-C₄ haloalkyl, —O—C₁-C₄ alkyl, —C₁-C₄ alkylene-O—C₁-C₄alkyl, optionally substituted heteroaryl, optionally substituted phenyl,optionally substituted cycloalkyl, and —OH; or R¹ is taken together withany ring atom in the piperazine moiety of formula (I) to form acarbocyclyl or heterocyclyl ring fused to the piperazine moiety.

In some embodiments, any alkyl, alkylene, cycloalkyl, or heterocyclylportion of R¹ is substituted with 1, 2, or 3 substituents independentlyselected from deuterium, halo, cyano, acetyl, C₁-C₄ alkyl, C₁-C₄haloalkyl, —O—C₁-C₄ alkyl, —C₁-C₄ alkylene-O—C₁-C₄ alkyl, optionallysubstituted heteroaryl, optionally substituted phenyl, optionallysubstituted cycloalkyl, —COOH, and —OH.

In some embodiments, R¹ is selected from —O—(C₀-C₃alkylene)-(N-containing heterocyclyl), —S—(C₀-C₃ alkylene)-(O-containingheterocyclyl), —NH—O—(C₁-C₃ alkyl), and —NH— phenyl, wherein any alkyl,alkylene, phenyl, or heterocyclyl portion of R¹ is unsubstituted, or issubstituted with 1, 2, or 3 substituents independently selected fromdeuterium, halo, cyano, acetyl, C₁-C₄ alkyl, C₁-C₄ haloalkyl, —O—C₁-C₄alkyl, —C₁-C₄ alkylene-O—C₁-C₄ alkyl, optionally substituted heteroaryl,optionally substituted phenyl, optionally substituted cycloalkyl, —COOH,and —OH.

In an embodiment, R¹ is selected from —C(O)—(C₁-C₃ alkyl), C₁-C₃ alkyl,—O—(C₁-C₃ alkyl), —NH(C₁-C₃ alkyl), —N(C₁-C₄ alkyl)₂, —NH—(C₃-C₆cycloalkyl), C₃-C₆ cycloalkyl, —O—(C₃-C₆ cycloalkyl), —O—(C₁-C₃alkyl)-(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)-(C₃-C₆ cycloalkyl), and anN-containing heterocyclyl, wherein any alkyl, cycloalkyl, orheterocyclyl portion of R¹ is unsubstituted, or is substituted with 1,2, or 3 substituents independently selected from halo, cyano, acetyl,C₁-C₄ alkyl, C₁-C₄ haloalkyl, —O—C₁-C₄ alkyl, —C₁-C₄ alkylene-O—C₁-C₄alkyl, optionally substituted heteroaryl, optionally substituted phenyl,optionally substituted cycloalkyl, and —OH; or R¹ is taken together withany ring atom in the piperazine moiety of formula (I) to form acarbocyclyl or heterocyclyl ring fused to the piperazine moiety.

In an embodiment, R¹ is selected from 1-(3-chlorophenyl)cyclopropyl,1-(3-fluorophenyl)cyclopropyl, 1-acetylcyclopropyl,1-cyclopropylcyclopropyl, 1-difluoromethylcyclopropyl,1-fluorocyclopropyl, 1-methylpropylamino, 1-pyridin-3-ylcyclopropyl,1-thiazol-2-ylcyclopropyl, 1-thien-2-ylcyclopropyl,1-trifluoromethylcyclopropyl, 2-(4-chlorophenyl)cyclopropyl,2,2,2-trifluoroethoxy, 2,2-difluorocyclopropyl, 2,2-dimethylcyclopropyl,2-cyanocyclopropyl, 2-cyanoethyl, 2-cyanoethylamino,2-cyclobutylcyclopropyl, 2-fluorocyclopropyl, 2-fluoroethoxy,2-hydroxyethylamino, 2-methoxyethoxy, 2-methylcyclopropyl,2-oxa-6-azaspiro[3.3]heptan-6-yl, 3,3-difluorocyclobutyl,3-cyanoazetidin-1-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl,3-hydroxy-3-methylcyclobutyl, 3-hydroxy-3-trifluoromethylcyclobutyl,3-hydroxyazetidin-1-yl, 3-hydroxycyclobutyl, 3-methoxyazetidin-1-yl,3-methoxymethylazetidin-1-yl, 3-phenyl-3-hydroxycyclobutyl,4-cyanocyclohexyl, 4-cyanoypiperidin-1-yl, 4-hydroxy-4-methylcyclohexyl,4-hydroxycyclohexyl, 4-hydroxypiperidin-1-yl, 4-methylcyclohexyl,acetyl, azetidin-1-yl, cyclobutoxy, cyclobutyl, cyclobutylamino,cyclopentylamino, cyclopropyl, cyclopropylmethyl, diethylamino, ethoxy,ethyl, ethylamino, isobutoxy, isopropoxy, isopropyl, isopropylamino,methoxymethyl, N-ethyl-N-methylamino, pentylamino, piperidin-1-yl,propylamino, propyloxypyrrolidin-1-yl, t-butylamino, t-butoxy,2,2-dimethylpropoxy, 2,2-difluoroethoxy, N-(2,2-dimethylpropyl)amino,N-(1,2-dimethylpropyl)amino, 2,2,2-trifluoroethylamino,N-(methoxymethyl)amino, oxetan-3-yloxy, oxetan-3-yl, oxetan-3-ylamino,oxetan-3-ylmethoxy, N-(oxetan-3-ylmethyl)amino, tetrahydrofuran-3-yloxy,tetrahydropyran-4-yloxy, and 3-cyanocyclobutoxy, or R¹ is taken togetherwith a ring atom in the piperazine moiety to form a6-oxohexahydropyrrolo[1,2-a]pyrazin-2-yl, or2-ethyl-3-oxohexahydroimidazo[1,5-a]pyrazin-7-yl.

In an embodiment, R¹ is selected from 1,3-dihydroxypropan-2-yloxy,1-acetylazetidin-3-yloxy, 1-hydroxy-2-hydroxycarbonylethan-2-yloxy,1-methyl-2-fluoroethoxy, 2,2-difluoroethylamino, 2-cyanoethan-1-yloxy,2-fluoroethylamino, 2-fluorophenylamino, 2-fluoropropoxy,2-methyloxetan-3-yloxy, 3-cyano-oxetan-3-yloxy,3-deutero-oxetan-3-yloxy, 6-oxa-1-azaspiro[3.3]heptan-1-yl,cyclopropoxy, ethoxyamino, oxetan-3-ylthio, perdeuteroethoxy,phenylamino, tetrahydrofuran-2-yloxy, and tetrahydrofuran-3-yl. In anembodiment, R¹ is selected from 1-(3-chlorophenyl)cyclopropyl,1-(3-fluorophenyl)cyclopropyl, 1-acetylcyclopropyl,1-cyclopropylcyclopropyl, 1-difluoromethylcyclopropyl,1-fluorocyclopropyl, 1-methylpropylaminol-pyridin-3-ylcyclopropyl,1-thiazol-2-ylcyclopropyl, 1-thien-2-ylcyclopropyl,1-trifluoromethylcyclopropyl, 2-(4-chlorophenyl)cyclopropyl,2,2,2-trifluoroethoxy, 2,2-difluorocyclopropyl, 2,2-dimethylcyclopropyl,2-cyanocyclopropyl, 2-cyanoethyl, 2-cyanoethylamino,2-cyclobutylcyclopropyl, 2-fluorocyclopropyl, 2-fluoroethoxy,2-hydroxyethylamino, 2-methoxyethoxy, 2-methylcyclopropyl,2-oxa-6-azaspiro[3.3]heptan-6-yl, 3,3-difluorocyclobutyl,3-cyanoazetidin-1-yl, 3-cyanocyclobutyl, 3-fluorocyclobutyl,3-hydroxy-3-methylcyclobutyl, 3-hydroxy-3-trifluoromethylcyclobutyl,3-hydroxyazetidin-1-yl, 3-hydroxycyclobutyl, 3-methoxyazetidin-1-yl,3-methoxymethylazetidin-1-yl, 3-phenyl-3-hydroxycyclobutyl,4-cyanocyclohexyl, 4-cyanoypiperidin-1-yl, 4-hydroxy-4-methylcyclohexyl,4-hydroxycyclohexyl, 4-hydroxypiperidin-1-yl, 4-methylcyclohexyl,acetyl, azetidin-1-yl, cyclobutoxy, cyclobutyl, cyclobutylamino,cyclopentylamino, cyclopropyl, cyclopropylmethyl, diethylamino, ethoxy,ethyl, ethylamino, isobutoxy, isopropoxy, isopropyl, isopropylamino,methoxymethyl, N-ethyl-N-methylamino, pentylamino, piperidin-1-yl,propylamino, propyloxypyrrolidin-1-yl, and t-butylamino, or R¹ is takentogether with a ring atom in the piperazine moiety to form a6-oxohexahydropyrrolo[1,2-a]pyrazin-2-yl, or2-ethyl-3-oxohexahydroimidazo[1,5-a]pyrazin-7-yl.

In an embodiment, R² is selected from halo, cycloalkyl, heterocyclyl,—O—(C₀-C₄ alkylene)-(heterocyclyl), —(C₁-C₃ alkylene)-heterocyclyl,—(C₁-C₃ alkylene)-NH—(C₁-C₃ alkyl), -(hydroxy-substituted C₁-C₃alkylene)-NH—(C₁-C₃ alkyl), C₁-C₃ alkyl substituted with both hydroxyand amino, and cyano-substituted C₁-C₄ alkyl, or R² is taken togetherwith a ring atom in ring A to form a heterocyclyl or a carbocyclyl thatis fused to ring A, wherein any heterocyclyl, cycloalkyl, or carbocyclylis optionally substituted with up to 3 substituents independentlyselected from halo, cyano, —NH₂, —NH(C₁-C₄ alkyl), —NH—C(O)—O—(C₁-C₄alkyl), ═O, —OH, —C(O)—C₁-C₄ alkyl, —C₁-C₄ alkyl, deuterated C₁-C₄alkyl, —C₁-C₄ haloalkyl, hydroxy-substituted —C₁-C₄ alkyl, —O—C₁-C₄alkyl, —(C₁-C₄ alkylene)-O—(C₁-C₄ alkyl), —(C₁-C₄ alkylene)-O—(C₁-C₄haloalkyl), —C(O)—O—C₁-C₄ alkyl, C₃-C₆ cycloalkyl, an optionallysubstituted second heterocyclyl, or —NH-(optionally substituted secondheterocyclyl).

In an embodiment R² is selected from —OH, —S(O)₂—C₁-C₄ alkyl, -(aminosubstituted C₁-C₃ alkylene)-heterocyclyl, C₄ alkyl, C₁-C₃ alkylsubstituted with both hydroxy and either C₁-C₄ alkylamino or di-C₁-C₄alkylamino.

In an embodiment, any heterocyclyl, cycloalkyl, or carbocyclyl isoptionally substituted with up to 3 substituents independently selectedfrom halo, cyano, —OH, —NH₂, —NH(C₁-C₄ alkyl), —NH—C(O)—O—(C₁-C₄ alkyl),═O, —OH, —C(O)—C₁-C₄ alkyl, —C₁-C₄ alkyl, deuterated C₁-C₄ alkyl, —C₁-C₄haloalkyl, hydroxy-substituted —C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —O—C₁-C₄haloalkyl, —(C₁-C₄ alkylene)-O—(C₁-C₄ alkyl), -(amino substituted C₁-C₄alkylene)-O—(C₁-C₄ alkyl), —(C₁-C₄ alkylene)-O—(C₁-C₄ haloalkyl),—C(O)—O—C₁-C₄ alkyl, —COOH, C₃-C₆ cycloalkyl, an optionally substitutedsecond heterocyclyl, or —NH-(optionally substituted secondheterocyclyl).

In an embodiment, R² is selected from halo, cycloalkyl, heterocyclyl,—O—(C₀-C₄ alkylene)-(heterocyclyl), and cyano-substituted C₁-C₄ alkyl,or R² is taken together with a ring atom in ring A to form aheterocyclyl that is fused to ring A, wherein any heterocyclyl isoptionally substituted with up to 3 substituents independently selectedfrom halo, —NH₂, ═O, —OH, —C(O)—C₁-C₄ alkyl, —C₁-C₄ alkyl, deuteratedC₁-C₄ alkyl, —C₁-C₄ haloalkyl, hydroxy-substituted —C₁-C₄ alkyl,—O—C₁-C₄ alkyl, —(C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), C₃-C₆ cycloalkyl, anoptionally substituted second heterocyclyl, or —NH-(optionallysubstituted second heterocyclyl).

In an embodiment, R² is selected from1-(1-hydroxypropan-2-yl)-4-methoxypiperidin-4-yl,1-(3-difluoromethoxy)propan-2-yl-4-methoxypiperidin-4-yl,1-(3-methoxy)propan-2-yl-4-methoxypiperidin-4-yl,1-(oxetan-3-yl)-4-methoxypiperidin-4-yl, 1-(oxetan-3-yl)piperidin-4-yl,1-(propan-2-yl)piperidin-3-yl, 1-(propan-2-yl)piperidin-4-yl,1-(pyrrolidin-1-yl)ethan-1-yl, 1,2,3,6-tetrahydropyridin-4-yl,1,4-diazabicyclo[4.2.0]octan-4-yl, 1-acetylpiperdin-4-yl,1-cyclobutylpiperidin-3-yl, 1-ethyl-3,3-difluoropiperidin-4-yl,1-ethyl-3-fluoropiperidin-4-yl, 1-ethyl-3-hydroxyazetidin-3-yl,1-ethyl-4-fluoropyrrolidin-3-yl, 1-ethylazetidin-3-yl,1-ethylazetidin-3-yloxy, 1-ethylpiperidin-3-yl,1-ethylpiperidin-3-yloxy, 1-ethylpiperidin-4-yl,1-ethylpiperidin-4-yloxy, 1-ethylpyrrolidin-3-yl,1-ethylpyrrolidin-3-ylmethoxy, 1-ethylpyrrolidin-3-yloxy,1H-pyrrolidin-2-yl, 1-hydroxy-2-aminoprop-2-yl,1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl,1-isopropyl-2-methylpyrrolidin-2-yl,1-isopropyl-3,4-dimethylpiperazin-3-yl,1-isopropyl-3-ethoxypiperidin-3-yl, 1-isopropyl-3-fluoropiperidin-3-yl,1-isopropyl-3-hydroxyazetidin-3-yl, 1-isopropyl-3-hydroxypiperidin-3-yl,1-isopropyl-3-hydroxypyrrolidin-3-yl,1-isopropyl-3-methoxyazetidin-3-yl, 1-isopropyl-3-methoxypiperidin-3-yl,1-isopropyl-3-methoxypyrrolidin-3-yl,1-isopropyl-3-methylpiperazin-3-yl, 1-isopropyl-4-cyanopiperidin-4-yl,1-isopropyl-4-ethoxypiperidin-4-yl, 1-isopropyl-4-fluoropiperidin-4-yl,1-isopropyl-4-fluoropyrrolidin-3-yl,1-isopropyl-4-hydroxypiperidin-3-yl,1-isopropyl-4-hydroxypiperidin-4-yl,1-isopropyl-4-methoxypiperidin-4-yl, 1-isopropyl-4-methylpiperazin-3-yl,1-isopropyl-4-methylpiperidin-4-yl,1-isopropyl-4-trifluoromethylpiperidin-4-yl,1-isopropyl-5-methylpyrrolidin-3-yl, 1-isopropylazetidin-2-ylmethoxy,1-isopropylazetidin-3-yl, 1-isopropylazetidin-3-ylmethoxy,1-isopropylazetidin-3-yloxy, 1-isopropylpiperazin-3-yl,1-isopropylpiperazin-4-yl, 1-isopropylpiperidin-2-yl,1-isopropylpiperidin-3-yl, 1-isopropylpiperidin-4-yl,1-isopropylpyrrolidin-2-yl, 1-isopropylpyrrolidin-3-yl,1-methyl-1-cyanoethyl, 1-sec-butylpiperidin-4-yl,1-t-butoxycarbonyl-4-aminopiperidin-4-yl,2-(isopropylamino)-3-hydroxypropan-2-yl, 2-(isopropylamino)-propan-2-yl,2,3,5,6-tetrahydroimidazo[2,1-b]thiazol-6-yl,2,6-diazaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.4]octan-2-yl,2,6-diazaspiro[3.4]octan-6-yl, 2,7-diazaspiro[4.4]nonan-2-yl,2-difluoromethylpiperazin-1-yl,2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl, 2-methyl-1H-pyrrolidin-2-yl,2-oxa-5,8-diazaspiro[3.5]nonan-8-yl, 2-oxo-4-ethylpiperazin-1-yl,2-oxopiperazin-1-yl, 2-trifluoromethylpiperazin-1-yl,3,3-difluoropiperidin-4-yl, 3,3-dimethyl-4-ethylpiperazin-1-yl,3-aminopyrrolidin-1-yl, 3-fluoropiperidin-3-yl, 3-fluoropiperidin-4-yl,3-hydroxyazetidin-3-yl, 3-hydroxyquinuclidin-3-yl,3-methyl-4-ethylpiperazin-1-yl, 3-methylpiperazin-1-yl,3-trifluoromethylpiperazin-1-yl,4-(1,1,2,2,2-pentadeuteroethyl)piperazin-1-yl,4-(2,2-difluoroethyl)piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,4-(2-methoxyethyl)piperazin-1-yl,4-(methoxycarbonylamino)piperidin-4-yl, 4-(oxetan-3-yl)piperazin-1-yl,4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-2-ylamino,4-aminopiperidin-1-yl, 4-cyanopiperidin-4-yl, 4-ethoxypiperidin-4-yl,4-ethylmorpholin-2-yl, 4-ethylpiperazin-1-yl,4-ethylpiperazin-1-ylethoxy, 4-fluoropiperidin-4-yl,4-fluoropyrrolidin-3-yl, 4-hydroxy-tetrahydro-2H-pyran-4-yl,4-isopropylmorpholin-3-yl, 4-isopropylpiperazin-1-yl,4-methoxypiperidin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperidin-4-yl,5,5-difluoropiperidin-3-yl, 5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl,6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl,6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl, 6-methylmorpholin-2-yl,azetidin-2-ylmethoxy, azetidin-3-yl, bromo, cyclopentyl,hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl,hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, morpholin-2-yl, morpholin-3-yl,octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, piperazin-1-yl,piperazin-1-ylethoxy, piperdin-4-yl, piperidin-2-yl, piperidin-3-yl,piperidin-3-yloxy, piperidin-4-yloxy, pyrrolidin-2-yl, pyrrolidin-3-yl,pyrrolidin-3-ylmethoxy, pyrrolidin-3-yloxy, quinuclidin-4-yl,tetrahydro-2H-pyran-4-yl, or R² is taken together with ring A to form3′H-spiro[azetidine-3,1′-isobenzofuran]-5′-yl,6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl,4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl,7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl,4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl, or5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,1-amino-2,3-dihydro-1H-inden-5-yl, or1-(isopropylamino)-2,3-dihydro-1H-inden-5-yl.

In an embodiment, R² is selected from1-(1-fluoropropan-2-yl)-4-ethoxypiperidin-4-yl,1-(1-fluoropropan-2-yl)-4-methoxypiperidin-4-yl,1-(2-fluoropropyl)-4-ethoxypiperidin-4-yl,1-(2-fluoropropyl)-4-ethoxypiperidin-4-yl,1-(3-(difluoromethoxy)propan-2-yl)-4-methoxypiperidin-4-yl,1-(oxetan-3-yl)-4-ethoxypiperidin-4-yl,1-(tetrahydrofuran-2-yl)-1-aminomethyl,1-amino-2-hydroxy-2-methylpropyl, 1-amino-2-methoxyethyl,1-azabicyclo[2.2.1]heptan-4-yl, 1-cyclopropyl-4-ethoxypiperidin-4-yl,1-diethylamino-2-hydroxyethyl, 1-ethylamino-2-hydroxyethyl,1-isopropyl-4-difluoromethoxypiperidin-3-yl,1-isopropyl-4-difluoromethoxypiperidin-4-yl,1-isopropyl-4-hydroxymethylpiperidin-4-yl,1-isopropyl-4-methoxycarbonylpiperidin-4-yl,1-isopropyl-4-(methoxymethyl)piperidin-4-yl,1-isopropyl-4-methoxypiperidin-4-yl,1-methyl-1-isopropylamino-2-hydroxyethyl,2,2,5,5-tetramethyl-4-hydroxypiperidin-4-yl,2,2-dimethyl-4-methoxypiperidin-4-yl, 2-amino-1-hydroxyethyl,2-amino-3-hydroxypropyl, 2-azaspiro[3.3]heptan-6-yl,2-hydroxy-1-aminoethyl, 2-hydroxy-1-isopropylaminoethyl,2-hydroxyethylaminomethyl, 3-amino-oxetan-3-yl, 3-ethoxypiperidin-3-yl,3-methoxypiperidin-3-yl, 4-amino-tetrahydropyran-4-yl,4-ethoxytetrahydropyran-4-yl, 4-hydroxycarbonylpiperidin-4-yl,4-hydroxymethylpiperidin-4-yl, 4-methoxycarbonylpiperidin-4-yl,4-methoxytetrahydropyran-4-yl, 4-trifluoromethylpiperidin-4-yl,ethylsulfonyl, and oxetan-3-ylaminomethyl.

In an embodiment, R² is selected from 1-(oxetan-3-yl)piperidin-4-yl,1-acetylpiperdin-4-yl, 1-cyclobutylpiperidin-3-yl,1-ethyl-3-fluoropiperidin-4-yl, 1-ethyl-3-hydroxyazetidin-3-yl,1-ethyl-4-fluoropyrrolidin-3-yl, 1-ethylazetidin-3-yl,1-ethylpiperidin-3-yl, 1-ethylpiperidin-4-yl, 1-ethylpyrrolidin-3-yl,1-isopropyl-3-hydroxyazetidin-3-yl, 1-isopropyl-3-hydroxypiperidin-3-yl,1-isopropylazetidin-3-yl, 1-isopropylpiperidin-3-yl,1-isopropylpiperidin-4-yl, 1-isopropylpyrrolidin-2-yl,1-isopropylpyrrolidin-3-yl, 1-methyl-1-cyanoethyl,2-difluoromethylpiperazin-1-yl, 2-oxo-4-ethylpiperazin-1-yl,2-oxopiperazin-1-yl, 2-trifluoromethylpiperazin-1-yl,3-fluoropiperidin-3-yl, 3-fluoropiperidin-4-yl, 3-hydroxyazetidin-3-yl,3-methyl-4-ethylpiperazin-1-yl, 3-methylpiperazin-1-yl,3-trifluoromethylpiperazin-1-yl, 4-(2-hydroxyethyl)-piperazin-1-yl,4-(oxetan-3-yl)piperazin-1-yl, 4-aminopiperidin-1-yl,4-ethylmorpholin-2-yl, 4-ethylpiperazin-1-yl, 4-fluoropyrrolidin-3-yl,4-hydroxy-tetrahydro-2H-pyran-4-yl, 4-isopropylpiperazin-1-yl,4-(2-methoxyethyl)piperazin-1-yl, 4-methylpiperazin-1-yl,6-methylmorpholin-2-yl, azetidin-3-yl, morpholin-2-yl, piperazin-1-yl,piperdin-4-yl, piperidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,tetrahydro-2H-pyran-4-yl, azetidin-2-ylmethoxy, pyrrolidin-3-yloxy,piperidin-2-yl, piperidin-3-yloxy, piperidin-4-yloxy,pyrrolidin-3-ylmethoxy, 1-ethylazetidin-3-yloxy,1-isopropylazetidin-3-yloxy, 1-ethylpyrrolidin-3-yloxy,1-isopropylazetidin-3-ylmethoxy, 1-isopropylazetidin-2-ylmethoxy,piperazin-1-ylethoxy, 4-(2-hydroxyethyl)piperazin-1-yl,1-isopropyl-4-fluoropyrrolidin-3-yl, 1-ethylpiperidin-4-yloxy,1-ethylpiperidin-3-yloxy, 1-ethylpyrrolidin-3-ylmethoxy,1-isopropyl-3-hydroxypyrrolidin-3-yl, 1-isopropylpiperidin-2-yl,1-isopropyl-4-hydroxypiperidin-4-yl, 4-ethylpiperazin-1-ylethoxy,1-sec-butylpiperidin-4-yl, 1-isopropyl-4-methoxypiperidin-4-yl,1-isopropyl-3-methoxypiperidin-3-yl, bromo, cyclopentyl,1,4-diazabicyclo[4.2.0]octan-4-yl,5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl,4-(1,1,2,2,2-pentadeuteroethyl)piperazin-1-yl,1-ethyl-3,3-difluoropiperidin-4-yl,hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl,octahydro-2H-pyrido[1,2-a]pyrazin-2-yl,hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl,4-(2,2-difluoroethyl)piperazin-1-yl, 2,6-diazaspiro[3.3]heptan-2-yl,3,3-difluoropiperidin-4-yl, 3,3-dimethyl-4-ethylpiperazin-1-yl,6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl,6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl,2,6-diazaspiro[3.4]octan-6-yl, 2,6-diazaspiro[3.4]octan-2-yl,2-oxa-5,8-diazaspiro[3.5]nonan-8-yl, 2,7-diazaspiro[4.4]nonan-2-yl,4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-2-ylamino, and5,5-difluoropiperidin-3-yl, or R² is taken together with ring A to form3′H-spiro[azetidine-3,1′-isobenzofuran]-5′-yl,6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl,4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl,7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl,4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl, or5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl.

In another aspect, the compound has formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein ring A, R¹ and R²are as defined as for Formula (I).

In an embodiment, ring A is selected from:

wherein:

-   -   “1” represents a portion of ring A bound to a        pyrrolo[1,2-b]pyridazine moiety;    -   “2” represents a portion of ring A bound to R²; and    -   ring A is substituted with 0, 1, 2, or 3 independently selected        substituents in addition to R²;    -   R¹ is selected from C₁-C₃ alkyl, —O—(C₁-C₅ alkyl), —NH(C₁-C₅        alkyl), —NH—(C₃-C₆ cycloalkyl), C₃-C₆ cycloalkyl, —O—(C₃-C₆        cycloalkyl), an N-containing heterocyclyl, —O—(C₀-C₃        alkylene)-(O-containing heterocyclyl), —NH—(C₀-C₃        alkylene)-(O-containing heterocyclyl), and an O-containing        heterocyclyl, wherein any alkyl, cycloalkyl, or heterocyclyl        portion of R¹ is unsubstituted, or is substituted with 1, 2, or        3 substituents independently selected from halo, cyano, C₁-C₄        alkyl, C₁-C₄ haloalkyl, —O—C₁-C₄ alkyl, and —OH;    -   R² is selected from heterocyclyl, —O—(C₀-C₄        alkylene)-(heterocyclyl), —(C₁-C₃ alkylene)-heterocyclyl,        —(C₁-C₃ alkylene)-NH—(C₁-C₃ alkyl), -(hydroxy-substituted C₁-C₃        alkylene)-NH—(C₁-C₃ alkyl), and C₁-C₃ alkyl substituted with        both hydroxy and amino, or R² is taken together with a ring atom        in ring A to form a heterocyclyl or a carbocyclyl that is fused        to ring A, wherein any heterocyclyl is unsubstituted, or is        substituted with 1, 2, or 3 substituents independently selected        from halo, cyano, —NH₂, —OH, —C₁-C₄ alkyl, deuterated C₁-C₄        alkyl, —C₁-C₄ haloalkyl, hydroxy-substituted —C₁-C₄ alkyl,        —O—C₁-C₄ alkyl, C₃-C₆ cycloalkyl, —NH(C₁-C₄ alkyl),        —NH—C(O)—O—(C₁-C₄ alkyl), —(C₁-C₄ alkylene)-O—(C₁-C₄ alkyl),        —(C₁-C₄ alkylene)-O—(C₁-C₄ haloalkyl), —C(O)—O—C₁-C₄ alkyl, and        an optionally substituted second heterocyclyl; and    -   R^(3a) is selected from hydrogen and C₁-C₄ alkyl.

In an embodiment of Formula Ia, ring A is selected from:

wherein:

-   -   “1” represents a portion of ring A bound to a        pyrrolo[1,2-b]pyridazine moiety;    -   “2” represents a portion of ring A bound to R²; and    -   ring A is substituted with 0, 1, 2, or 3 independently selected        substituents in addition to R2;    -   R¹ is selected from C₁-C₃ alkyl, —O—(C₁-C₃ alkyl), —NH(C₁-C₃        alkyl), —NH—(C₃-C₆ cycloalkyl), C₃-C₆ cycloalkyl, —O—(C₃-C₆        cycloalkyl), and an N-containing heterocyclyl, wherein any        alkyl, cycloalkyl, or heterocyclyl portion of R¹ is        unsubstituted, or is substituted with 1, 2, or 3 substituents        independently selected from halo, cyano, C₁-C₄ alkyl, C₁-C₄        haloalkyl, and —OH;    -   R² is selected from heterocyclyl, and —O—(C₀-C₄        alkylene)-(heterocyclyl), or R² is taken together with a ring        atom in ring A to form a heterocyclyl that is fused to ring A,        wherein any heterocyclyl is unsubstituted, or is substituted        with 1, 2, or 3 substituents independently selected from halo,        —OH, —C₁-C₄ alkyl, deuterated C₁-C₄ alkyl, —C₁-C₄ haloalkyl,        —O—C₁-C₄ alkyl, and C₃-C₆ cycloalkyl; and    -   R^(3a) is selected from hydrogen and C₁-C₄ alkyl.

In another embodiment of Formula Ia, ring A is selected from:

wherein:

-   -   “1” represents a portion of ring A bound to a        pyrrolo[1,2-b]pyridazine moiety;    -   “2” represents a portion of ring A bound to R²; and    -   ring A is substituted with 0, 1, 2, or 3 independently selected        substituents in addition to R²;    -   R¹ is selected from C₁-C₃ alkyl, —O—(C₁-C₃ alkyl), —NH(C₁-C₃        alkyl), —NH—(C₃-C₆ cycloalkyl), C₃-C₆ cycloalkyl, —O—(C₃-C₆        cycloalkyl), an N-containing heterocyclyl, —O—(O-containing        heterocycle), and —O—(N-containing heterocycle), wherein any        alkyl, cycloalkyl, or heterocyclyl portion of R¹ is        unsubstituted, or is substituted with 1, 2, or 3 substituents        independently selected from deuterium, halo, cyano, C₁-C₄ alkyl,        C₁-C₄ haloalkyl, and —OH; R² is selected from heterocyclyl, and        —O—(C₀-C₄ alkylene)-(heterocyclyl), or R² is taken together with        a ring atom in ring A to form a heterocyclyl that is fused to        ring A, wherein any heterocyclyl portion of R² is unsubstituted,        or is substituted with 1, 2, or 3 substituents independently        selected from halo, —CN, —OH, —C₁-C₅ alkyl optionally        substituted with one or more —OH and/or one or more —NH₂,        deuterated C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —O—C₁-C₄ alkyl, and        C₃-C₆ cycloalkyl; and    -   R^(3a) is selected from hydrogen and C₁-C₄ alkyl.

In an embodiment, ring A is optionally substituted with up to 1substituent in addition to R², wherein the substituent, if present, ishalo or methyl. In an embodiment, ring A is optionally substituted withup to 1 substituent in addition to R², wherein the substituent, ifpresent, is halo.

In an embodiment, R¹ is selected from 2,2,2-trifluoroethoxy,2,2,2-trifluoroethylamino, 2,2-difluoroethoxy, 2,2-dimethylcyclopropyl,2,2-dimethylpropoxy, 2-cyanocyclopropyl, 2-cyanoethyl,2-cyanoethylamino, 2-fluorocyclopropyl, 2-methylcyclopropyl,3-cyanoazetidin-1-yl, 3-cyanocyclobutoxy, 3-cyanocyclobutyl,3-fluorocyclobutyl, 3-hydroxy-3-methylcyclobutyl,3-hydroxy-3-trifluoromethylcyclobutyl, 3-hydroxyazetidin-1-yl,3-hydroxycyclobutyl, 4-cyanocyclohexyl, 4-hydroxycyclohexyl,4-methylcyclohexyl, cyclobutoxy, cyclobutyl, cyclobutylamino,cyclopropyl, ethoxy, ethylamino, isopropoxy, isopropylamino,N-(1,2-dimethylpropyl)amino, N-(2,2-dimethylpropyl)amino,N-(methoxymethyl)amino, N-(oxetan-3-ylmethyl)amino, oxetan-3-yl,oxetan-3-ylamino, oxetan-3-ylmethoxy, oxetan-3-yloxy, propylamino,t-butoxy, tetrahydrofuran-3-yloxy, and tetrahydropyran-4-yloxy.

In an embodiment, R¹ is selected from 2,2,2-trifluoroethoxy,2,2-dimethylcyclopropyl, 2-cyanocyclopropyl, 2-cyanoethyl,2-fluorocyclopropyl, 2-methylcyclopropyl, 3-cyanoazetidin-1-yl,3-cyanocyclobutyl, 3-fluorocyclobutyl, 3-hydroxy-3-methylcyclobutyl,3-hydroxy-3-trifluoromethylcyclobutyl, 3-hydroxyazetidin-1-yl,3-hydroxycyclobutyl, 4-cyanocyclohexyl, 4-hydroxycyclohexyl,4-methylcyclohexyl, cyclobutoxy, cyclobutyl, cyclobutylamino,cyclopropyl, ethoxy, ethylamino, isopropoxy, isopropylamino, andpropylamino.

In an embodiment, R² is selected from1-(1-hydroxypropan-2-yl)-4-methoxypiperidin-4-yl,1-(3-difluoromethoxy)propan-2-yl-4-methoxypiperidin-4-yl,1-(3-methoxy)propan-2-yl-4-methoxypiperidin-4-yl,1-(oxetan-3-yl)-4-methoxypiperidin-4-yl, 1-(propan-2-yl)piperidin-3-yl,1-(propan-2-yl)piperidin-4-yl, 1-(pyrrolidin-1-yl)ethan-1-yl,1,2,3,6-tetrahydropyridin-4-yl, 1-cyclobutylpiperidin-3-yl,1-ethyl-3-fluoropiperidin-4-yl, 1-ethyl-3-hydroxyazetidin-3-yl,1-ethyl-4-fluoropyrrolidin-3-yl, 1-ethylazetidin-3-yl,1-ethylazetidin-3-yloxy, 1-ethylpiperidin-3-yl,1-ethylpiperidin-3-yloxy, 1-ethylpiperidin-4-yl, 1-ethylpyrrolidin-3-yl,1-ethylpyrrolidin-3-ylmethoxy, 1-ethylpyrrolidin-3-yloxy,1H-pyrrolidin-2-yl, 1-hydroxy-2-aminoprop-2-yl,1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl,1-isopropyl-2-methylpyrrolidin-2-yl,1-isopropyl-3,4-dimethylpiperazin-3-yl,1-isopropyl-3-ethoxypiperidin-3-yl, 1-isopropyl-3-fluoropiperidin-3-yl,1-isopropyl-3-hydroxyazetidin-3-yl, 1-isopropyl-3-hydroxypiperidin-3-yl,1-isopropyl-3-hydroxypyrrolidin-3-yl,1-isopropyl-3-methoxyazetidin-3-yl, 1-isopropyl-3-methoxypiperidin-3-yl,1-isopropyl-3-methoxypyrrolidin-3-yl,1-isopropyl-3-methylpiperazin-3-yl, 1-isopropyl-4-cyanopiperidin-4-yl,1-isopropyl-4-ethoxypiperidin-4-yl, 1-isopropyl-4-fluoropiperidin-4-yl,1-isopropyl-4-fluoropyrrolidin-3-yl,1-isopropyl-4-hydroxypiperidin-3-yl,1-isopropyl-4-hydroxypiperidin-4-yl,1-isopropyl-4-methoxypiperidin-4-yl, 1-isopropyl-4-methylpiperazin-3-yl,1-isopropyl-4-methylpiperidin-4-yl,1-isopropyl-4-trifluoromethylpiperidin-4-yl,1-isopropyl-5-methylpyrrolidin-3-yl, 1-isopropylazetidin-3-yl,1-isopropylpiperazin-3-yl, 1-isopropylpiperazin-4-yl,1-isopropylpiperidin-2-yl, 1-isopropylpiperidin-3-yl,1-isopropylpiperidin-4-yl, 1-isopropylpyrrolidin-2-yl,1-isopropylpyrrolidin-3-yl, 1-sec-butylpiperidin-4-yl,1-t-butoxycarbonyl-4-aminopiperidin-4-yl,2-(isopropylamino)-3-hydroxypropan-2-yl, 2-(isopropylamino)-propan-2-yl,2,3,5,6-tetrahydroimidazo[2,1-b]thiazol-6-yl,2-difluoromethylpiperazin-1-yl,2-isopropyl-2,6-diazaspiro[3.3]heptan-6-yl, 2-methyl-1H-pyrrolidin-2-yl,3-aminopyrrolidin-1-yl, 3-fluoropiperidin-3-yl,3-hydroxyquinuclidin-3-yl, 3-methyl-4-ethylpiperazin-1-yl,3-methylpiperazin-1-yl, 4-(1,1,2,2,2-pentadeuteroethyl)piperazin-1-yl,4-(methoxycarbonylamino)piperidin-4-yl, 4-cyanopiperidin-4-yl,4-ethoxypiperidin-4-yl, 4-ethylpiperazin-1-yl, 4-fluoropiperidin-4-yl,4-fluoropyrrolidin-3-yl, 4-isopropylmorpholin-3-yl,4-isopropylpiperazin-1-yl, 4-methoxypiperidin-4-yl,4-methylpiperidin-4-yl, 6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl,6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl, azetidin-2-ylmethoxy,hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, morpholin-2-yl, morpholin-3-yl,piperazin-1-yl, piperdin-4-yl, piperidin-2-yl, piperidin-3-yl,piperidin-3-yloxy, pyrrolidin-2-yl, pyrrolidin-3-yloxy, andquinuclidin-4-yl, or

R² is taken together with ring A to form6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl,5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,1-amino-2,3-dihydro-1H-inden-5-yl, or1-(isopropylamino)-2,3-dihydro-1H-inden-5-yl.

In an embodiment, R² is selected from 1-cyclobutylpiperidin-3-yl,1-ethyl-3-fluoropiperidin-4-yl, 1-ethyl-3-hydroxyazetidin-3-yl,1-ethyl-4-fluoropyrrolidin-3-yl, 1-ethylazetidin-3-yl,1-ethylazetidin-3-yloxy, 1-ethylpiperidin-3-yl,1-ethylpiperidin-3-yloxy, 1-ethylpiperidin-4-yl, 1-ethylpyrrolidin-3-yl,1-ethylpyrrolidin-3-ylmethoxy, 1-ethylpyrrolidin-3-yloxy,1-isopropyl-3-hydroxyazetidin-3-yl, 1-isopropyl-3-hydroxypiperidin-3-yl,1-isopropyl-3-methoxypiperidin-3-yl,1-isopropyl-4-fluoropyrrolidin-3-yl,1-isopropyl-4-hydroxypiperidin-4-yl,1-isopropyl-4-methoxypiperidin-4-yl, 1-isopropylazetidin-3-yl,1-isopropylpiperidin-2-yl, 1-isopropylpiperidin-3-yl,1-isopropylpiperidin-4-yl, 1-isopropylpyrrolidin-2-yl,1-isopropylpyrrolidin-3-yl, 1-sec-butylpiperidin-4-yl,2-difluoromethylpiperazin-1-yl, 3-fluoropiperidin-3-yl,3-methyl-4-ethylpiperazin-1-yl, 3-methylpiperazin-1-yl,4-(1,1,2,2,2-pentadeuteroethyl)piperazin-1-yl, 4-ethylpiperazin-1-yl,4-fluoropyrrolidin-3-yl, 4-isopropylpiperazin-1-yl,6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl,6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl, azetidin-2-ylmethoxy,hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, morpholin-2-yl, piperazin-1-yl,piperdin-4-yl, piperidin-2-yl, piperidin-3-yl, piperidin-3-yloxy,pyrrolidin-2-yl, and pyrrolidin-3-yloxy, or

R² is taken together with ring A to form6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl, or5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl.

In an embodiment, R^(3a) is selected from hydrogen and methyl.

In an embodiment, ring A is substituted with 0 or 1 substituent inaddition to R², wherein the substituent, if present, is halo.

In an alternate embodiment, ring A is substituted with 0 or 1substituent in addition to R², wherein the substituent, if present, isselected from chloro, fluoro, and methyl.

In yet another embodiment, the compound is a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is C(R¹³) or N;    -   R¹¹ is selected from —NH—(C₃-C₄ cycloalkyl); —NH—C₁-C₃ alkyl;        —O—C₃-C₄ cycloalkyl; —O—C₁-C₃ alkyl optionally substituted with        one or more substituents selected from fluoro, hydroxy, —CN, and        deuterium; and —O—(O-containing heterocycle);    -   R¹² is selected from piperidin-3-yl optionally 3-substituted        with C₁-C₃ alkoxy, fluoro, C₁-C₃ alkyl, or —CN; and        piperidin-4-yl optionally 4-substituted with C₁-C₃ alkoxy,        fluoro, C₁-C₃ alkyl, —CN, wherein R¹² is additionally optionally        1-substituted with C₁-C₅ alkyl optionally substituted with one        or more —OH and/or one or more —NH₂;    -   R¹³ is selected from hydrogen, —CN and fluoro; and    -   R¹⁴, if present, is fluoro.

In certain embodiments of Formula II, the compound is a compound ofFormula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, R¹¹, R¹⁴, and subvariables thereof are as defined in Formula        II;        The term “subvariables” as used herein means the variables that        are used to define a variable. For example, X is C(R¹³); R₁₃ is        a subvariable of X.    -   R¹⁵ is selected from hydrogen, C₁-C₃ alkoxy, fluoro, C₁-C₃        alkyl, and —CN; and    -   R¹⁶ is C₁-C₅ alkyl optionally substituted with one or more —OH        and/or one or more —NH₂.

In certain embodiments of Formula II, the compound is a compound ofFormula IIb:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, R¹¹, R¹⁴, and subvariables thereof are as defined in Formula        II;    -   R¹⁵ is selected from hydrogen, C₁-C₃ alkoxy, fluoro, C₁-C₃        alkyl, and —CN; and    -   R¹⁶ is C₁-C₅ alkyl optionally substituted with one or more —OH        and/or one or more —NH₂.

In certain embodiments of a compound of Formula IIb, the compound is acompound of Formula IIb-1:

or a pharmaceutically acceptable salt thereof, wherein X, R¹¹, R¹², R¹⁴,R¹⁵ R¹⁶, and subvariables thereof are as defined in Formula IIb.

In certain embodiments of a compound of Formula IIb, the compound is acompound of Formula IIb-2:

or a pharmaceutically acceptable salt thereof, wherein X, R¹¹, R¹², R¹⁴,R¹⁵ R¹⁶, and subvariables thereof are as defined in Formula IIb.

In certain embodiments of Formula II, IIa, IIb, IIb-1 and IIb-2, R¹⁴ isabsent.

In certain embodiments of Formula II, IIa, IIb, IIb-1 and IIb-2, R¹³ ishydrogen.

In certain embodiments of Formula II, IIa, IIb, IIb-1 and IIb-2, R¹¹ isselected from —NH—C₁-C₃ alkyl; —O—C₁-C₃ alkyl optionally substitutedwith one or more substituents selected from fluoro, hydroxy, —CN, anddeuterium; oxetan-3-yl and tetrahydrofuran-3-yl. In some aspects ofthese embodiments, R¹¹ is selected from —OCH₂CH₃, —NHCH(CH₃)₂,oxetan-3-yl and tetrahydrofuran-3-yl.

In certain embodiments the compound is a compound of Formula I orFormula Ia that is not a compound of any of Formula II, IIa, IIb, IIb-1or IIb-2.

In an embodiment, the compound is a compound of any of Formulae I, la,II, II, IIb, IIb-1, or IIb-2 selected from a compound in Table 1.

In another aspect, the present disclosure features a pharmaceuticalcomposition comprising a compound of any of Formulae I, la, II, II, IIb,IIb-1, or IIb-2 described herein (e.g., a compound in Table 1) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Table 1 below shows the structures of compounds described herein.

TABLE 1 LCMS # Structure (M + 1) NMR 100

392 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (s, 1H), 7.94 (s, 1H),7.88 (s, 1H), 7.86 (d, 1H, J = 5.2 Hz), 6.85 (s, 1H), 5.96 (d, 1H, J =5.2 Hz), 5.18-5.13 (m, 1H), 3.92-3.88 (m, 4H), 3.74 (t, 2H, J = 8.0 Hz),3.70-3.68 (m, 2H), 3.55-3.45 (m, 5H), 2.02-2.00 (m, 1H), 0.77-0.73 (m,4H). 101

392 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.04 (d, 1H, J = 1.6 Hz),7.95 (d, 1H, J = 5.2 Hz), 6.92 (d, 1H, J = 1.6 Hz), 6.70 (s, 1H), 6.01(d, 1H, J = 5.2 Hz), 4.09 (t, 2H, J = 5.2 Hz), 3.93-3.90 (m, 4H),3.72-3.68 (m, 2H), 3.57-3.55 (m, 2H), 3.52-3.47 (m, 2H), 3.06 (t, 2H, J= 5.2 Hz), 2.04-1.99 (m, 1H), 0.78-0.72 (m, 4H). 102

402 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.93 (s, 1H), 7.85 (d, 1H, J =5.2 Hz), 7.63 (d, 2H, J = 8.4 Hz), 7.36 (d, 2H, J = 8.4 Hz), .6.72 (s,1H) 5.85 (d, 1H, J = 5.2 Hz), 4.00-3.90 (m, 4H), 3.90-3.80 (m, 4H),3.57-3.50 (m, 2H), 3.50- 3.40 (m, 2H), 1.85-1.80 (m, 1H), 1.79-1.73 (m,1H), 1.06-1.04 (m, 2H), 0.85-0.81 (m, 2H). 103

405 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.12 (s, 1H), 7.94 (s, 1H),7.86 (d, 1H, J = 5.2 Hz), 7.80 (s, 1H), 6.83 (s, 1H), 5.96 (d, 1H, J =5.2 Hz), 4.68 (quintet, 1H, J = 9.0 Hz), 3.92-3.43 (m, 8H), 2.11-2.06(m, 2H), 2.04-2.02 (m, 1H), 1.97-1.93 (m, 2H), 1.83-1.78 (m, 2H), 1.68-1.64 (m, 2H), 0.79-0.73 (m, 4H). 104

406 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (s, 1H), 7.95 (s, 1H),7.91 (s, 1H), 7.86 (d, 1H, J = 5.2 Hz), 6.83 (s, 1H), 5.96 (d, 1H, J =5.2 Hz), 5.09-5.05 (br. s, 1H), 3.94-3.86 (m, 2H), 3.72- 3.66 (m, 2H),3.55-3.42 (m, 6H), 3.27-3.20 (m, 2H), 2.38-2.32 (m, 1H), 2.25-2.21 (m,1H), 2.10-2.00 (m, 1H), 0.77-0.73 (m, 4H). 105

406 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.98 (s, 1H), 7.89 (d, 1H, J= 5.2 Hz), 7.78 (s, 1H), 6.86 (s, 1H), 6.61 (s, 1H), 5.97 (d, 1H, J =5.2 Hz), 4.91-4.77 (m, 1H), 3.96-3.90 (m, 2H), 3.74-3.68 (m, 2H),3.57-3.53 (m, 2GH), 3.47- 3.43 (m., 2H), 3.18-3.11 (m, 1H), 3.10-3.02(m, 1H), 3.01-2.94 (m, 1H), 2.90-2.80 (m, 1H), 2.34-2.23 (m, 1H),2.22-2.14 (m, 1H), 2.08- 1.95 (m, 2H), 0.83-0.68 (m, 4H). 106

406 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 2.0 Hz),7.94 (d, 1H, J = 5.6 Hz), 6.93 (d, 1H, J = 2.0 Hz), 6.72 (s, 1H), 6.02(d, 1H, J = 5.6 Hz), 4.21 (t, 2H, J = 5.6 Hz), 3.93-.90 (m, 2H),3.72-3.68 (m, 2H), 3.60-3.52 (m, 4H), 3.49-3.45 (m, 2H), 2.76 (t, 2H, J= 5.6 Hz), 2.38 (s, 3H), 2.04-1.99 (m, 1H), 0.79-0.74 (m, 4H). 107

408 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 7.86 (d, 1H, J = 5.6 Hz), 7.83(d, 1H, J = 1.6 Hz), 7.09 (s, 1H), 6.77 (d, 1H, J = 1.6 Hz), 6.02 (d,1H, J = 5.6 Hz), 4.24 (s, 2H), 4.05-3.92 (m, 2H), 3.90-3.77 (m, 2H),3.70-3.60 (m, 2H), 3.59- 3.49 (m, 2H), 3.35 (t, 2H, J = 6.0 Hz), 2.89(t, 2H, J = 6.0 Hz), 2.05-1.97 (m, 1H), 0.95-0.91 (m, 2H), 0.89-0.85 (m,2H). 108

409 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.32 (s, 1H), 7.98 (d, 1H, J= 5.6 Hz), 7.18 (s, 1H), 6.03 (d, 1H, J = 5.6 Hz), 4.05-3.80 (m, 2H),3.75-3.65 (m, 2H), 3.65-3.55 (m, 2H), 3.50- 3.40 (m, 2H), 3.27-3.24 (m,2H), 2.81-2.76 (m, 2H), 2.05-2.97 (m, 1H), 1.97-1.8 (m, 2H), 0.79- 0.74(m, 4H). 109

409 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 8.10 (d, 1H, J = 1.6 Hz), 7.91(d, 1H, J = 5.2 Hz), 7.04 (d, 1H, J = 1.6 Hz), 6.04 (d, 1H, J = 6.0 Hz),4.10-3.95 (m, 4H), 3.95-3.75 (m, 2H), 3.70- 3.60 (m, 2H), 3.60-3.50 (m,2H), 3.19 (t, 2H, J = 6.0 Hz), 2.89 (t, 2H, J = 6.0 Hz), 2.05-1.97 (m,1H), 0.99-0.85 (m, 2H), 0.85-0.80 (m, 2H). 110

414 111

415 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.32 (d, 1H, J = 1.2 Hz),7.97 (d, 2H, J = 8.0 Hz), 7.92 (d, 1H, J = 5.6 Hz), 7.88 (d, 2H, J = 8.0Hz), 7.18 (d, 1H, J = 1.2 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.93-3.92 (m,2H), 3.73-3.67 (m, 2H), 3.57-3.53 (m, 2H), 3.51-3.47 (m, 2H), 3.49- 3.33(m, 4H), 2.04-1.99 (m, 1H), 0.78-0.72 (m, 4H). 112

416 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.89 (d, 1H, J= 6.0 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.31 (d, 2H, J = 7.6 Hz), 7.04 (s,1H), 5.97 (d, 1H, J = 5.2 Hz), 3.92-3.91 (m, 2H), 3.69-3.68 (m, 2H),3.53-3.47 (m, 4H), 3.43- 3.41 (m, 1H), 3.41-3.38 (m, 1H), 3.30-3.28 (m,1H), 3.09-3.06 (m, 1H), 2.89-2.84 (m, 1H, J = 10.0 Hz), 2.25-2.22 (m,1H), 2.03-2.00 (m, 1H), 1.83-1.82 (m, 1H), 0.78-0.74 (m, 4H). 113

417 114

420 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.25 (d, 1H, J = 2.0 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.88 (d, 2H, J = 8.4 Hz), 7.57 (d, 2H, J = 8.4Hz), 7.10 (d, 1H, J = 1.6 Hz), 6.58 (br s, 1H), 5.99 (d, 1H, J = 5.6Hz), 4.25 (d, 2H, J = 10.8 Hz), 4.02 (d, 2H, J = 10.4 Hz), 3.95-3.90 (m,2H), 3.73-3.68 (m, 1H), 3.60-3.50 (m, 2H), 3.50- 3.40 (m, 2H), 2.06-2.00(m, 1H), 0.79-0.75 (m, 4H). 115

418 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.11 (s, 1H), 7.89 (d, 1H, J= 5.6 Hz), 7.73 (d, 2H, J = 8.4 Hz), 6.98 (s, 1H), 6.84 (d, 2H, J = 8.4Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.05-4.98 (m, 1H), 3.97-3.92 (m, 3H),3.75-3.70 (m, 2H), 3.68- 3.61 (m, 2H), 3.53-3.49 (m, 2H), 3.45-3.41 (m,2H), 2.04-1.98 (m, 1H), 0.78-0.74 (m, 4H). 116

420 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.83 (d, 1H, J = 5.6 Hz), 7.76(d, 1H, J = 1.6 Hz), 7.74 (s, 1H), 7.68 (s, 1H), 6.53 (d, 1H, J = 1.6Hz), 5.84 (d, 1H, J = 5.6 Hz), 4.33-4.23 (m, 1H), 4.00-3.83 (m, 4H),3.60-3.40 (m, 5H), 3.13- 3.03 (m, 2H), 2.80-2.70 (m, 1H), 2.33-2.23 (m,1H), 2.10-1.98 (m, 1H), 1.82-1.76 (m, 2H), 1.72-1.64 (m, 1H), 1.09-1.03(m, 2H), 0.88- 0.80 (m, 2H). 117

420 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.11 (s, 1H), 7.92 (d, 1H, J= 1.6 Hz), 7.85 (d, 2H, J = 5.2 Hz), 7.80 (s, 1H), 6.82 (d, 1H, J = 1.6Hz), 5.95 (d, 1H, J = 5.2 Hz), 4.18-4.13 (m, 1H), 3.91-3.90 (m, 2H),3.69-3.68 (m, 2H), 3.50- 3.43 (m, 3H), 3.05-3.02 (m, 2H), 2.61-2.55 (m,2H), 2.04-1.96 (m, 3H), 1.81-1.73 (m, 2H), 0.78-0.72 (m, 4H). 118

420 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26- 8.24 (m, 2H), 7.96 (s,1H), 7.91 (s, 1H), 7.88 (d, 1H, J = 5.2 Hz), 6.86 (s, 1H), 5.97 (d, 1H,J = 4.8 Hz), 5.00 (br. s., 1H), 4.30-2.80 (m, 4H), 3.97-3.91 (m, 2H),3.85-3.75 (m, 2H), 3.70-3.65 (m, 2H), 3.52-3.50 (m, 2H), 2.59 (q, 2H, J= 6.4 Hz), 2.03-2.01 (m, 1H), 0.95 (t, 3H, J = 6.4 Hz), 0.77-0.74 (m,4H). 119

425 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.92 (d, 1H, J = 1.6 Hz), 7.86(d, 1H, J = 5.6 Hz), 7.53- 7.51 (m, 4H), 6.69 (d, 1H, J = 1.6 Hz), 5.85(d, 1H, J = 5.6 Hz), 3.94-3.90 (m, 4H), 3.56- 3.49 (m, 4H), 1.81-1.74(m, 1H), 1.06-1.03 (m, 2H), 0.86-0.82 (m, 2H). 120

430 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 8.01 (d, 1H, J = 1.6 Hz), 7.85(d, 1H, J = 5.2 Hz), 7.83 (d, 1H, J = 8.0 Hz), 7.72 (d, 1H, J = 8.0 Hz),7.67 (s, 1H), 6.96 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.2 Hz), 5.17(s, 2H), 4.40-4.30 (m, 4H), 4.10-3.95 (m, 2H), 3.85-3.75 (m, 2H),3.66-3.57 (m, 2H), 3.55-3.50 (m, 2H), 2.05- 1.97 (m, 1H), 0.95-0.87 (m,2H), 0.85-0.80 (m, 2H). 121

430 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (s, 1H), 7.88 (d, 1H, J= 4.8 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.05-6.95 (m, 2H), 6.94 (s, 1H),5.96 (d, 1H, J = 5.6 Hz), 3.95-3.90 (m, 2H), 3.75- 3.65 (m, 2H),3.58-3.50 (m, 2H), 3.50-3.40 (m, 2H), 3.45-3.20 (m, 4H), 2.05-11.95 (m,1H), 0.78-0.74 (m, 4H). 122

430 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H), J =8.0 Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.2 Hz), 3.91 (br.s., 2H), 3.70 (br., s., 2H), 3.53- 3.46 (m, 4H), 3.05-3.02 (m, 2H),2.62-2.49 (m, 3H), 2.05-1.99 (m, 1H), 1.76-1.70 (m, 2H), 1.58-1.48 (m,2H), 0.80-0.70 (m, 4H). 123

430 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.0Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.00-3.80 (m,2H), 3.78-3.62 (m, 2H), 3.60-3.42 (m, 4H), 3.40-3.20 (m, 2H), 3.00- 2.90(m, 2H), 2.60-2.54 (m, 2H), 2.10-1.93 (m, 1H), 1.90-1.80 (m, 1H),1.70-1.40 (m, 3H), 1.80-0.60 (m, 4H). 124

430 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.61 (s, 1H), 7.94 (s, 1H),7.87 (d, 1H, J = 4.8 Hz), 7.66 (d, 2H, J = 8.0 Hz), 7.31 (d, 2H, J = 8.0Hz), 6.71 (s, 1H), 5.86 (d, 1H, J = 4.8 Hz), 4.41-4.39 (m, 2H),4.21-4.17 (m, 1H), 3.96- 3.90 (m, 2H), 3.95-3.90 (m, 2H), 3.76-3.75 (m,2H), 3.57-3.54 (m, 2H), 3.51-3.48 (m, 2H), 3.07 (q, 2H, J = 6.4 Hz),1.79-1.78 (m, 1H), 1.25 (t, 3H, J = 6.4 Hz), 1.11-1.05 (m, 2H),0.85-0.83 (m, 2H). 125

431 1H-NMR (H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.3 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.0 Hz,2H), 6.71 (d, J = 1.9 Hz, H), 5.84 (d, J = 5.4 Hz, 1H), 3.91 (d, J =19.0 Hz, 5H), 3.68-3.42 (m, 7H), 3.21 (d, J = 11.7 Hz, 2H), 2.82 (t, J =11.1 Hz, 1H), 1.94-1.75 (m, 3H), 1.04 (dt, J = 6.5, 3.2 Hz, 2H), 0.82(dq, J = 7.1, 3.8 Hz, 2H). 126

431 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 7.6Hz), 7.03 (d, 1H, J = 1.2 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.97-3.95 (m,4H), 3.71-3.70 (m, 2H), 3.55-3.52 (m, 2H), 3.48-3.41 (m, 4H), 2.78- 2.77(m, 1H), 2.04-2.00 (m, 1H), 1.73-1.70 (m, 4H), 0.79-0.75 (m, 4H). 127

431 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.06 (d, 1H, J = 1.2 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.64 (d, 2H, J = 8.4 Hz), 7.00-6.85 (m, 3H),5.95 (d, 1H, J = 5.6 Hz), 3.91 (br. s. 2H), 3.69 (br. s. 2H), 3.52 (br.s. 2H), 3.44 (br. s. 2H), 3.06- 3.04 (m, 4H), 2.82 (br. s. 4H),2.05-1.95 (m, 1H), 0.80-0.65 (m, 4H). 128

432 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.71- 7.69 (m, 2H), 7.34 (t, 1H, J = 7.6 Hz),7.21 (d, 1H, J = 7.6 Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6Hz), 4.43-4.41 (m, 1H), 3.91- 3.89 (m, 3H), 3.71 (br. s., 2H), 3.64-3.32(m, 5H), 3.00-2.96 (m, 1H), 2.76-2.75 (m, 2H), 2.65-2.55 (m, 1H),2.05-1.99 (m, 1H), 0.78- 0.74 (m, 4H). 129

432 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.95 (d, 1H, J = 5.6 Hz), 4.40-4.36 (m,1H), 3.89-3.87 (m, 3H), 3.69-3.46 (m, 8H), 2.94-2.90 (m, 1H), 2.75- 2.73(m, 2H), 2.55-2.49 (m, 1H), 2.05-1.97 (m, 1H), 0.77-0.71 (m, 4H). 130

432 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.38 (dd, 1H, J= 9.6, 1.6 Hz), 3.92-3.87 (m, 3H), 3.75-3.65 (m, 2H), 3.64-3.40 (m, 5H),3.38-3.35 (m, 1H), 2.92 (dd, 1H, J = 12.0, 2.0 Hz), 2.76-2.70 (m, 2H),2.52-2.50 (m, 1H), 2.05-1.99 (m, 1H), 0.80-0.72 (m, 4H). 131

432 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 4.40-4.35 (m,1H), 3.95-3.87 (m, 3H), 3.80-3.63 (m, 2H), 3.61-3.40 (m, 5H), 2.94- 2.91(m, 1H), 2.75-2.73 (m, 2H), 2.52-2.50 (m, 1H), 2.05-1.99 (m, 1H),0.80-0.72 (m, 4H). 132

432 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.11 (s, 1H), 7.88 (d, 1H, J= 5.2 Hz), 7.73 (d, 2H, J = 8.4 Hz), 6.99 (s, 1H), 6.96 (d, 2H, J = 8.4Hz), .5.96 (d, 1H, J = 5.2 Hz), 4.19-4.12 (m, 1H), 4.02-3.97 (m, 2H),3.95-3.90 (m, 2H), 3.75- 3.68 (m, 2H), 3.54-3.48 (m, 4H), 3.31-3.29 (m,2H), 2.30-2.25 (m., 1H), 2.14-2.07 (m, 1H), 2.04-1.97 (m, 1H), 0.78-0.74(m, 4H). 133

432 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.09 (s, 1H), 7.87 (d, 1H, J= 5.2 Hz), 7.71 (d, 2H, J = 8.4 Hz), 6.97 (s, 1H), 6.91 (d, 2H, J = 8.4Hz), 5.96 (d, 1H, J = 6.0 Hz), 4.90-4.85 (m, 1H), 3.94-3.89 (m, 2H),3.73-3.65 (m, 2H), 3.55- 3.50 (m, 2H), 3.10-3.05 (m, 2H), 2.92-2.85 (m,2H), 2.85-2.76 (m, 2H), 2.04-1.99 (m, 2H), 1.82-1.74 (m, 1), 0.77-0.74(m, 4H). 134

432 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.12 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.75 (d, 2H, J = 8.8 Hz), 6.98 (d, 3H, J = 8.8Hz), 5.97 (d, 1H, J = 5.6 Hz), 4.14 (d, 2H, J = 6.8 Hz), 3.95-3.90 (m,2H), 3.75-3.70 (m, 2H), 3.66 (d, 2H, J = 8.0 Hz), 3.55-3.50 (m, 2H),3.49-3.45 (m, 2H), 3.44-3.40 (m, 2H), 3.09- 2.99 (m, 1H), 2.05-2.01 (m,1H), 0.78-0.75 (m, 4H). 135

432 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 8.52 (d, 1H, J = 2.4 Hz),7.87-7.84 (m, 2H), 7.74 (dd, 1H, J = 2.4, 8.8 Hz), 6.71 (d, 1H, J = 8.8Hz), 6.63 (d, 1H, J = 2.0 Hz), 5.85 (d, 1H, J = 5.6 Hz), 3.94-3.87 (m,4H), 3.56-3.47 (m, 8H), 3.03-3.00 (m, 4H), 1.80-1.76 (m, 1H), 1.07- 1.03(m, 2H), 0.85-0.81 (m, 2H). 136

433 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (d, 1H, J = 1.2 Hz),7.86 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.8Hz), 6.91 (d, 1H, J = 1.2 Hz), 5.94 (d, 1H, J = 5.2 Hz), 3.66-3.65 (m,4H), 3.49-3.48 (m, 2H), 3.42-3.41 (m, 4H), 3.15-3.14 (m, 4H), 2.52- 2.51(m, 2H), 2.38 (q, 2H, J = 7.2 Hz), 2.06 (s, 3H), 1.03 (t, 3H, J = 7.2Hz). 137

434 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.8Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.30-5.00 (m,1H), 4.00-3.85 (m, 2H), 3.75-23.65 (m, 2H), 3.60-3.40 (m, 6H), 3.20-3.10 (m, 1H), 3.08-3.00 (m, 1H), 2.75-2.65 (m, 1H), 2.05-1.95 (m, 1H),0.80-0.70 (m, 4H). 138

434 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.97 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.2 Hz), 7.78 (d, 1H, J = 2.4 Hz), 6.86 (d, 1H, J = 1.6Hz), 7.96 (d, 1H, J = 5.2 Hz), 6.62 (d, 1H, J = 2.4 Hz), 5.96 (d, 1H, J= 5.2 Hz), 4.92-4.85 (m, 1H), 3.92 (br. s., 2H), 3.69 (br. s., 2H),3.53- 3.44 (m, 4H), 2.85 (q, 2H, J = 7.2 Hz), 2.807- 2.77 (m, 1H),2.48-2.42 (m, 3H), 2.39-2.30 (m, 1H), 2.13-2.06 (m, 1H), 2.04-1.97 (m,1H), 1.04 (t, 3H, J = 7.2 Hz), 0.78-0.73 (m, 4H). 139

434 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (s, 1H), 7.93 (d, 1H, J= 1.2 Hz), 7.85 (d, 1H, J = 5.2 Hz), 7.81 (s, 1H), 6.83 (d, 1H, J = 1.2Hz), 5.95 (d, 1H, J = 5.2 Hz), 4.87-4.85 (m, 1H), 3.91-3.90 (m, 2H),3.68-3.67 (m, 2H), 3.50- 3.49 (m, 4H), 3.43-3.34 (m, 4H), 2.91-2.90 (m,1H), 2.76-2.74 (m, 2H), 2.08-2.07 (m, 1H), 2.02-1.98 (m, 1H), 1.04 (t,3H, J = 7.2 Hz), 0.77-0.74 (m, 4H). 140

434 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.4Hz), 6.91 (d, 1H, J = 1.6 Hz), 6.60 (t, 1H, J = 5.6 Hz), 5.96 (d, 1H, J= 5.6 Hz), 3.52-3.51 (m, 4H), 3.43-3.41 (m, 4H), 3.12-3.09 (m, 2H),3.10-3.05 (m, 4H), 2.86-2.83 (m, 4H), 1.04 (t, 3H, J = 6.8 Hz). 141

435 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 7.99 (s, 1H), 7.86 (m, 1H), 7.78(d, 2H, J = 8.0 Hz), 6.93 (s, 1H), 7.45 (d, 2H, J = 8.0 Hz), 6.96 (s,1H), 6.00 (d, 1H, J = 5.6 Hz), 4.79-4.70 (m, 1H), 4.29-4.25 (m, 1H),4.04-3.97 (m, 1H), 3.67-3.64 (m, 4H), 3.56-3.54 (m, 4H), 3.50- 3.47 (m,1H), 3.39-3.34 (m, 2H), 3.25-3.21 (m, 2H), 3.18-3.14 (m, 1H), 1.54 (t,3H, J = 7.2 Hz). 142

435 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 7.99 (s, 1H), 7.85 (m, 1Hz),7.77 (d, 2H, J = 8.4 Hz), 7.44 (d, 2H, J = 8.0 Hz), 6.93 (s, 1H), 6.00(d, 1H, J = 5.2 Hz), 4.79-3.77 (m, 1H), 4.28-4.25 (m, 1H), 4.05-3.98 (m,1H), 3.66-3.64 (m, 4H), 3.55-3.53 (m, 4H), 3.49-3.47 (m, 1H), 3.39- 3.40(m, 2H), 3.27-3.22 (m, 2H), 3.16-3.14 (m, 1H), 1.53 (t, 3H, J = 7.2 Hz).143

435 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.29 (br. s., 1H), 8.07 (d,1H, J = 1.2 Hz), 7.87 (d, 1H, J = 5.6 Hz), 7.66 (d, 2H, J = 8.4 Hz),6.96 (d, 2H, J = 8.4 Hz), 6.92 (d, 1H, J = 1.2 Hz), 5.96 (d, 1H, J = 5.6Hz), 4.08 (q, 2H, J = 6.8 Hz), 3.65-3.55 (m, 4H), 3.50-3.40 (m, 4H),3.20-3.10 (m, 4H), 3.05-2.90 (m, 4H), 1.21 (t, 3H, J = 6.8 Hz). 144

436 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 0.8 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 0.8 Hz), 5./97 (d, 1H, J = 5.6 Hz), 4.40-4.35 (m,1H), 4.08 (q, 2H, J = 7.2 Hz), 3.90-3.80 (m, 1H), 3.65-3.60 (m, 1H),3.61-3.56 (m, 4H), 3.48-3.40 (m, 4H), 3.00- 2.90 (m, 1H), 2.80-2.70 (m,2H), 2.60-2.40 (m, 1H), 1.21 (t, 3H, J = 7.2 Hz). 145

438 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.40-5.00 (m,1H), 4.08 (q, 2H, J = 7.2 Hz), 3.70-3.50 (m, 4H), 3.50-3.47 (m, 2H),3.45-3.40 (m, 4H), 3.20-3.15 (m, 1H), 3.12- 3.05 (m, 1H), 2.85-2.75 (m,1H), 1.21 (t, 3H, J = 7.2 Hz). 146

443 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.31 (s, 1H), 8.04 (d, 1H, J= 1.2 Hz), 7.86 (d, 1H, J = 5.2 Hz), 7.62 (d, 2H, J = 8.4 Hz), 6.91 (d,1H, J = 1.2 Hz), 6.47 (d, 2H, J = 8.4 Hz), 5.95 (d, 1H, J = 5.2 Hz),4.17-407 (m, 4H), 4.01-3.95 (m, 4H), 3.95-3.90 (m, 2H), 3.73-3.65 (m,2H), 3.52-3.51 (m, 2H), 3.46-3.44 (m, 2H), 2.05- 1.99 (m, 1H), 0.80-0.72(m, 4H). 147

444 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (s, 1H), 7.90 (d, 1H, J= 5.6 Hz), 7.74 (d, 2H, J = 8.0 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.03 (s,1H), 5.97 (d, 1H, J = 5.6 Hz), 3.93-3.91 (m, 2H), 3.70-3.68 (m, 2H),3.54-3.48 (m, 5H), 3.11- 3.10 (m, 1H), 2.84-2.83 (m, 2H), 2.67-2.62 (m,3H), 2.28-2.25 (m, 1H), 2.04-2.01 (m, 1H), 1.86-1.81 (m, 1H), 1.11 (t,3H, J = 6.8 Hz), 0.79-0.73 (m, 4H). 148

444 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 3.92-3.91 (m,2H), 3.70-3.69 (m, 2H), 3.53-3.47 (m, 4H), 3.29-3.25 (m, 1H), 2.93- 2.89(m, 1H), 2.68-2.62 (m, 2H), 2.47-2.40 (m, 2H), 2.24-2.20 (m, 2H),2.03-1.98 (m, 1H), 1.78-1.73 (m, 1H), 1.05 (t, 3H, J = 7.2 Hz),0.78-0.72 (m, 4H). 149

444 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.2 Hz), 5.97 (d, 1H, J = 5.6 Hz), 3.92-3.91 (m,2H), 3.70-3.69 (m, 2H), 3.53-3.47 (m, 5H), 2.95-2.91 (m, 1H), 2.70- 2.63(m, 2H), 2.47-2.40 (m, 2H), 2.24-2.20 (m, 2H), 2.03-1.98 (m, 1H),1.77-1.75 (m, 1H), 1.05 (t, 3H, J = 7.6 Hz), 0.78-0.74 (m, 4H). 150

444 1H-NMR (H-NMR (400 MHz, MeOD) δ 7.99 (d, 1H, J = 1.6 Hz), 7.85 (d,1H, J = 5.6 Hz), 7.78 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4 Hz),6.95 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 4.40-4.32 (m, 2H),4.10-4.02 (m, 5H), 3.88-3.82 (m, 2H), 3.65-3.60 (m, 2H), 3.58- 3.52 (m,2H), 3.38-3.32 (m, 1H), 2.07-2.00 (m, 1H), 1.24 (d, 6H, J = 6.4 Hz),0.96-0.92 (m, 2H), 0.92-0.84 (m, 2H). 151

445 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.81 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.92 (br. s,2H), 3.70-3.65 (m, 4H), 3.55- 3.50 (m, 4H), 3.34 (s, 2H), 3.01 (t, 2H, J= 5.2 Hz), 2.00 (quintet, 1H, J = 5.2 Hz), 0.79- 0.75 (m, 4H). 152

445 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.06 (s, 1H), 7.85 (d, 1H, J= 5.2 Hz), 7.62 (d, 2H, J = 8.4 Hz), 6.93 (d, 2H, J = 8.4 Hz), 6.86 (s,1H), 5.92 (d, 1H, J = 5.2 Hz), 4.65 (br. s., 1H), 4.25-4.10 (m, 1H),4.00-3.80 (m, 2H), 3.40- 3.20 (m, 4H), 3.10-3.00 (m, 4H), 2.90-2.70 (m,4H), 2.05-1.90 (m, 1H), 1.45-1.20 (m, 3H), 0.75 (br. s., 4H). 153

445 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.87 (d, 1H, J = 1.6 Hz), 7.83(d, 1H, J = 5.6 Hz), 7.57 (d, 2H, J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz),6.66 (d, 1H, J = 0.8 Hz), 5.83 (d, 1H, J = 5.2 Hz), 3.95-3.89 (m, 4H),3.56-3.47 (m, 4H), 3.29-3.27 (m, 4H), 2.66-2.23 (m, 4H), 2.40 (s, 3H),1.82-1.75 (m, 1H), 1.06-1.04 (m, 2H), 0.84-0.82 (m, 2H). 154

445 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.08 (s, 1H), 7.87 (d, 1H, J= 5.6 Hz), 7.67 (d, 2H, J = 8.4 Hz), 6.97 (d, 2H, J = 8.8 Hz), 6.94 (s,1H), 5.96 (d, 1H, J = 5.2 Hz), 3.68-3.03 (m, 17H), 2.23-2.11 (m, 4H),1.93-1.90 (m, 1H), 1.78- 1.77 (m, 1H). 155

445 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 1.6 Hz),7.87 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.4Hz), 6.94 (s, 1H), 5.96 (d, 1H, J = 5.6 Hz), 3.94- 3.92 (m, 2H),3.71-3.69 (m, 2H), 3.55-3.53 (m, 4H), 3.47-3.45 (m, 3H), 3.00-2.97 (m,1H), 2.84-2.81 (m, 2H), 2.57-2.56 (m, 1H), 2.25- 2.20 (m, 1H), 2.02-2.01(m, 1H), 1.05 (d, 3H, J = 6.4 Hz), 0.78-0.75 (m, 4H). 156

445 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.64 (d, 2H, J = 8.8 Hz), 6.94 (d, 2H, J = 8.8Hz), 6.93 (s, 1H), 5.94 (d, 1H, J = 5.6 Hz), 3.92- 3.91 (m, 2H),3.71-3.70 (m, 2H), 3.58-3.45 (m, 7H), 3.01-2.98 (m, 1H), 2.86-2.85 (m,2H), 2.58-2.57 (m, 1H), 2.27-2.21 (m, 1H), 2.01- 1.99 (m, 1H), 1.05 (d,3H, J = 6.4 Hz), 0.78- 0.74 (m, 4H). 157

445 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.07 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.8Hz), 6.91 (d, 1H, J = 1.6 Hz), 6.03 (d, 1H, J = 5.6 Hz), 4.14-4.05 (m,1H), 4.04-3.96 (m, 1H), 3.95-3.88 (m, 1H), 3.86-3.74 (m, 1H), 3.50- 3.38(m, 4H), 3.20-3.10 (m, 4H), 3.09-3.00 (m, 1H), 2.85-2.75 (m, 1H),2.70-2.60 (m, 1H), 2.36 (q, 2H, J = 7.2 Hz), 2.33-2.25 (m, 2H),2.20-2.10 (m, 1H), 1.70-1.55 (m, 1H), 1.03 (t, 3H, J = 7.2 Hz). 158

445 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.63 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.8Hz), 6.94-6.92 (m, 1H), 5.95 (d, 1H, J = 5.6 Hz), 3.92-3.91 (m, 2H),3.67-3.64 (m, 4H), 3.54- 3.40 (m, 4H), 3.40-3.35 (m, 1H), 2.75-2.69 (m,4H), 2.02-2.01 (m, 1H), 1.80-1.77 (m, 2H), 1.35-1.22 (m, 2H), 0.77-0.73(m, 4H). 159

446 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.87 (d, 1H, J = 2.0 Hz), 7.84(d, 1H, J = 5.2 Hz), 7.56 (d, 2H, J = 8.8 Hz), 6.97 (d, 2H, J = 8.8 Hz),6.66 (d, 1H, J = 2.0 Hz), 5.84 (d, 1H, J = 5.2 Hz), 4.46 (heptet, 1H, J= 3.6 Hz), 3.99-3.90 (m, 2H), 3.90-3.81 (m, 2H), 3.61-3.50 (m, 2H),3.50-3.39 (m, 2H), 3.23-3.18 (m, 1H), 2.92- 2.85 (m, 2H), 2.72-.75 (m,1H), 2.07-2.00 (m, 1H), 1.88-1.75 (m, 3H), 1.58-1.50 (m, 1H), 1.07-1.02(m, 2H), 0.86-0.80 (m, 2H). 160

446 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.88 (d, 1H, J = 1.6 Hz), 7.84(d, 1H, J = 5.2 Hz), 7.59 (d, 2H, J = 8.8 Hz), 6.96 (d, 2H, J = 8.8 Hz),6.65 (d, 1H, J = 1.6 Hz), 5.85 (d, 1H, J = 5.2 Hz), 4.67-4.61 (m, 1H),3.99-3.90 (m, 2H), 3.90-3.75 (m, 2H), 3.60-3.50 (m, 2H), 3.50- 3.40 (m,2H), 3.41-3.33 (m, 2H), 3.19-3.15 (m, 2H), 2.25-2.08 (m, 4H), 1.79-1.75(m, 1H), 1.06-1.02 (m, 2H), 0.85-0.80 (m, 2H). 161

446 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 2.0 Hz),8.17 (s, 1H), 7.91 (d, 1H, J = 5.2 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.61(d, 2H, J = 8.4 Hz), 7.06 (d, 1H, J = 1.2 Hz), 6.09 (br s, 1H), 5.99 (d,1H, J = 5.2 Hz), 3.96-3.92 (m, 2H), 3.79-3.77 (m, 2H), 3.73-3.68 (m,2H), 3.57-3.52 (m, 2H), 3.47-3.45 (m, 4H), 2.72 (q, 2H, J = 6.8 Hz),2.06-1.98 (m, 1H), 0.98 (t, 3H, J = 6.8 Hz), 0.79-0.74 (m, 4H). 162

446 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.87 (d, 1H, J = 2.0 Hz), 7.84(d, 1H, J = 5.2 Hz), 7.56 (d, 2H, J = 8.8 Hz), 6.97 (d, 2H, J = 8.8 Hz),6.66 (d, 1H, J = 2.0 Hz), 5.84 (d, 1H, J = 5.2 Hz), 4.46 (heptet, 1H, J= 3.6 Hz), 3.99-3.90 (m, 2H), 3.90-3.81 (m, 2H), 3.61-3.50 (m, 2H),3.50-3.39 (m, 2H), 3.23-3.18 (m, 1H), 2.92- 2.85 (m, 2H), 2.82-.75 (m,1H), 2.07-2.00 (m, 1H), 1.88-1.75 (m, 3H), 1.58-1.50 (m, 1H), 1.07-1.02(m, 2H), 0.86-0.80 (m, 2H). 163

446 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.87 (d, 1H, J = 2.0 Hz), 7.84(d, 1H, J = 5.2 Hz), 7.56 (d, 2H, J = 8.8 Hz), 6.97 (d, 2H, J = 8.8 Hz),6.66 (d, 1H, J = 2.0 Hz), 5.84 (d, 1H, mJ = 5.2 Hz), 4.46 (heptet, 1H, J= 3.6 Hz), 3.99-3.90 (m, 2H), 3.90-3.81 (m, 2H), 3.61-3.50 (m, 2H),3.50-3.39 (m, 2H), 3.23-3.18 (m, 1H), 2.92- 2.85 (m, 2H), 2.82-.75 (m,1H), 2.07-2.00 (m, 1H), 1.88-1.75 (m, 3H), 1.58-1.50 (m, 1H), 1.07-1.02(m, 2H), 0.86-0.80 (m, 2H). 164

446 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.33 (d, 1H, J = 8.0Hz), 7.05 (s, 1H), 5.98 (d, 1H, J = 5.6 Hz), 4.44 (d, 1H, J = 9.2 Hz),3.95-3.90 (m, 2H), 3.73=3.69 (m, 2H), 3.69-3.68 (m, 1H), 3.57-3.54 (m,2H), 3.49-3.46 (m, 2H), 2.90 (d, 1H, J = 14 Hz), 2.80 (d, 1H, J = 14Hz), 2.50-2.45 (m, 1H), 2.35 (t, 1H, J = 14 Hz), 2.05-2.00 (m, 1H), 1.11(d, 3H, J = 6.0 Hz), 0.78-0.74 (m, 4H). 165

446 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.33 (d, 1H, J = 8.0Hz), 7.05 (s, 1H), 5.98 (d, 1H, J = 5.6 Hz), 4.44 (d, 1H, J = 9.2 Hz),3.95-3.90 (m, 2H), 3.73=3.69 (m, 2H), 3.69-3.68 Z(m, 1H), 3.57-3.54 (m,2H), 3.49-3.46 (m, 2H), 2.90 (d, 1H, J = 14 Hz), 2.80 (d, 1H, J = 14Hz), 2.50-2.45 (m, m1H), 2.35 (t, 1H, J = 14 Hz), 2.05-2.00 (m, 1H),1.11 (d, 3H, J = 6.0 Hz), 0.78-0.74 (m, 4H). 166

446 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.34 (s, 1H), 8.12 (d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.2 Hz), 7.75 (d, 2H, J = 8.4 Hz), 6.99 (s,1H), 6.97 (d, 2H, J = 8.4 Hz), 5.97 (d, 1H, J = 5.2 Hz), 4.04-4.01 (m,2H), 3.99-3.92 (m, 2H), 3.71-3.70 (m, 2H), 3.55-3.51 (m, 2H), 3.49- 3.45(m, 2H), 3.33-3.31 (m, 1H), 3.29-3.23 (m, 1H), 3.15-3.14 (m, 1H),3.00-2.99 (m, 1H), 2.73-2.71 (m, 1H), 2.04-2.02 (m, 1H), 2.02- 2.00 (m,1H), 1.80-1.75 (m, 1H), 0.79-0.75 (m, 4H). 167

446 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (s, 1H), 8,12 (d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.8 Hz), 6.98 (d,1H, J = 1.6 Hz), 6.87 (d, 2H, J = 8.8 Hz), 5.97 (d, 1H, J = 5.6 Hz),4.89-3.86 (m, 1H), 3.94-3.92 (m, 4H), 3.56-3.51 (m, 4H), 3.47-3.45 (m,2H), 3.22-3.20 (m, 2H), 2.64 (q, 2H, J = 7.2 Hz), 2.04-2.00 (m, 1H),0.95 (t, 3H, J = 7.2 Hz), 0.79-0.73 (m, 4H). 168

446 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (s, 1H), 7.90 (d, 1H, J= 5.6 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.38 (d, 1H, J = 8.4 Hz), 7.05 (s,1H), 5.98 (d, 1H, J = 5.6 Hz), 4.75-4.70 (m, 1H), 3.95-3.90 (m, 2H),3.73-3.68 (m, 2H), 3.57- 3.52 (m, 2H), 3.50-3.45 (m, 2H), 2.95-2.90 (m,1H), 2.85-2.80 (m, 1H), 2.79-2.70 (m, 1H), 2.50-2.34 (m, 1H), 2.03-1.99(m, 1H), 1.27 (d, 3H, J = 6.0 Hz), 0.78-0.74 (m, 4H). 169

446 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.22 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.40 (d, 2H, J = 8.4Hz), 7.07 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.75-4.70 (m,1H), 3.95-3.90 (m, 2H), 3.73-3.69 (m, 2H), 3.58-3.54 (m, 2H), 3.50- 3.45(m, 2H), 3.23-3.19 (m, 1H), 3.08-3.05 (m. 1H), 3.04-3.01 (m, 1H),2.84-2.80 (m, 1H), 2.10-2.01 (m, 1H), 2.01-1.98 (m, 1H), 1.33 (d, 3H, J= 7.2 Hz), 0.78-0.74 (m, 4H). 170

446 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.63 (d, 1H, J = 2.0 Hz),8.16 (d, 1H, J = 2.0 Hz), 8.01 (dd, 1H, J = 8.8, 2.4 Hz), 7.87 (d, 1H, J= 5.2 Hz), 7.00-6.90 (m, 2H), 5.95 (d, 1H, J = 5.2 Hz), 4.63 (br. s.,1H), 4.25-4.10 (m, 1H), 4.00- 3.80 (m, 2H), 3.65 (br. s., 4H), 3.27 (br.s., 4H), 3.08 (br. s., 4H), 2.05-1.90 (m, 1H), 1.45- 1.20 (m, 3H),0.80-0.65 (m, 4H). 171

447 172

447 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 8.0 Hz), 7.50 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.2 Hz), 5.98 (d, 1H, J = 5.6 Hz), 5.02 (s, 1H),3.92-3.93 (m, 2H), 3.80-3.70 (m, 6H), 3.55-3.48 (m, 4H), 2.03-1.94 (m,3H), 1.57-1.54 (m, 2H), 0.79-0.75 (m, 4H). 173

447 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.06 (br. s., 1H), 7.87 (br.s., 1H), 7.64-7.53 (m, 3H), 6.94 (br. s., 2H), 5.94 (br. s., 1H), 3.67(br. s., 4H), 3.47-3.33 (m, 4H), 3.16 (br. s., 4H), 2.50-2.48 (m, 4H),2.31 (br. s., 4H), 1.03 (d, 6H, J = 4.0 Hz). 174

448 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ 8.16 (d, 1H, J = 1.2 Hz), 7.89(d, 1H, J = 5.2 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.0 Hz),7.03 (d, 1H, J = 1.2 Hz), 5.96 (d, 1H, J = 5.2 Hz), 4.68-4.50 (m, 1H),3.91 (br. s., 2H), 3.70 (br. s., 2H), 3.54 (br. s., 2H), 3.43 (br. s.,2H), 3.29-3.25 (m, 1H), 2.90-2.87 (m, 1H), 2.77- 2.64 (m, 1H), 2.53-2.51(m, 1H), 2.48-2.45 (m, 1H), 2.05-1.99 (m, 1H), 1.77-1.74 (m, 1H),1.67-1.57 (m, 1H), 0.79-0.71 (m, 4H). 175

448 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.94 (d, 1H, J = 2.0 Hz),7.86 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.0Hz), 6.72 (d, 1H, J = 2.0 Hz), 5.85 (d, 1H, J = 5.6 Hz), 4.71-4.52 (m,1H), 3.94-3.90 (m, 4H), 3.57-3.52 (m, 4H), 3.13-3.10 (m, 1H), 2.86- 2.67(m, 3H), 1.98-1.95 (m, 1H), 1.27 (s, 1H), 1.08-1.02 (m, 2H), 0.86-0.82(m, 2H). 176

448 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.94 (d, 1H, J = 2.0 Hz),7.86 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.0Hz), 6.72 (d, 1H, J = 2.0 Hz), 5.85 (d, 1H, J = 5.2 Hz), 4.73-4.52 (m,1H), 3.94-3.90 (m, 4H), 3.57-3.52 (m, 4H), 3.13-3.10 (m, 1H), 2.86- 2.67(m, 3H), 2.05-1.96 (m, 2H), 1.86-1.72 (m, 2H), 1.08-1.02 (m, 2H),0.86-0.82 (m, 2H). 177

448 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H), J = 2.0 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4Hz), 7.07 (d, 1H, J = 2.0 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.95-3.90 (m,2H), 3.73-3.68 (m, 2H), 3.58-3.50 (m, 2H), 3.49-3.40 (m, 2H), 2.99- 2.78(m, 3H), 2.65-2.60 (m, 1H), 2.22-2.15 (m, 1H), 2.10-1.95 (m, 2H),l1.82-1.67 (m, 1H), 1.60-1.49 (m, 1H), 0.80-0.73 (m, 4H). 178

448 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.21 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4Hz), 7.07 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.95-3.90 (m,2H), 3.73-3.68 (m, 2H), 3.57-3.53 (m, 2H), 3.50-3.42 (m, 2H), 2.99- 2.95(m, 2H), 2.94-2.90 (m, 1H), 2.55-2.51 (m, 1H), 2.22-2.10 (m, 1H),2.05-1.95 (m, 2H), 1.82-1.65 (m, 1H), 1.60-1.45 (m, 1H), 0.80- 0.73 (m,4H). 179

448 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.21 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4Hz), 7.07 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.95-3.90 (m,2H), 3.73-3.68 (m, 2H), 3.57-3.53 (m, 2H), 3.50-3.42 (m, 2H), 2.99- 2.95(m, 2H), 2.94-2.90 (m, 1H), 2.55-2.51 (m, 1H), 2.22-2.10 (m, 1H),2.05-1.95 (m, 2H), 1.82-1.65 (m, 1H), 1.60-1.45 (m, 1H), 0.80- 0.73 (m,4H). 180

464 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 8.65 (s, 1H), 7.92 (d, 1H, J =1.6 Hz), 7.85 (d, 1H, J = 5.6 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.31 (d,2H, J = 8.4 Hz), 6.68 (d, 1H, J = 1.2 Hz), 5.85 (d, 1H, J = 4.8 Hz),4.20 (q, 2H, J = 7.2 Hz), 3.81- 3.70 (m, 4H), 3.67-3.55 (m, 2H),3.49-3.40 (m, 4H), 3.39-3.35 (m, 1H), 3.26-3.14 (m, 1H), 3.10-3.00 (m,2H), 2.99-2.95 (m, 1H), 2.51- 2.42 (m, 1H), 2.21-2.08 (m, 1H), 1.34 (t,3H, J = 7.2 Hz), 131 (t, 3H, J = 7.2 Hz). 181

448 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (s, 1H), 7.89 (d, 1H, J= 5.6 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 6.98 (s,1H), 5.97 (d, 1H, J = 5.6 Hz), 4.08 (q, 2H, J = 7.2 Hz), 3.70-3.55 (m,4H), 3.50-3.40 (m, 4H), 3.30-3.20 (m, 1H), 2.91 (t, 1H, J = 8.4 Hz),2.75-2.68 (m, 1H), 2.68-2.57 (m, 1H), 2.50- 2.47 (m, 1H), 2.44 (q, 2H, J= 7.2 Hz), 2.25- 2.10 (m, 1H), 1.80-1.65 (m, 1H), 1.21 (t, 3H, J = 7.2Hz), 1.04 (t, 3H, J = 7.2 Hz). 182

448 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 7.97 (d, 1H, J = 1.6 Hz), 7.85(d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.36 (d, 2H, J = 8.0 Hz),6.90 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.2 Hz), 4.18 (q, 2H, J = 7.2Hz), 4.06-4.00 (m, 2H), 3.90-3.80 (m, 1H), 3.77-3.71 (m, 4H), 3.56-3.52(m, 2H), 3.52-3.47 (m, 4H), 2.90- 2.80 (m, 1H), 1.30 (t, 3H, J = 7.2Hz), 1.10 (d, 6H, J = 6.0 Hz). 183

448 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (s, 1H), 7.84-7.81 (m,3H), 6.80 (d, 1H, J = 1.2 Hz), 6.00 (d, 1H, J = 4.0 Hz), 4.23-4.21 (m,1H), 4.04-4.03 (m, 2H), 3.86-3.85 (m, 2H), 3.62-3.53 (m, 4H), 3.17-3.14(m, 2H), 2.54 (q, 2H, J = 7.2 Hz), 2.25-2.12 (m, 2H), 2.12-2.04 (m, 7H),1.17 (t, 3H, J = 7.2 Hz), 0.95-0.92 (m, 2H), 0.89-0.86 (m, 2H). 184

449 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.07 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.8 Hz), 6.95 (s, 1H), 6.94(d, 2H, J = 8.8 Hz), 5.97 (d, 1H, J = 5.6 Hz), 4.98-4.68 (m, 1H),4.00-3.86 (m, 2H), 3.78-3.61 (m, 2H), 3.61-3.48 (m, 2H), 3.47-3.40 (m,2H), 3.14- 2.97 (m, 4H), 2.91-2.78 (m, 4H), 2.72-2.59 (m, 1H), 2.35-2.29(m, 1H), 1.52-1.34 (m, 1H), 1.25-1.11 (m, 1H). 185

449 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.07 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.8 Hz), 6.96 (s, 1H), 6.94(d, 2H, J = 8.8 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.08-4.83 (m, 1H),4.00-3.82 (m, 2H), 3.80-3.66 (m, 2H), 3.63-3.54 (m, 2H), 3.53-3.45 (m,2H), 3.16- 3.04 (m, 4H), 2.93-2.80 (m, 4H), 2.27-2.16 (m, 1H), 1.62-1.48(m, 1H), 1.12-0.98 (m, 1H). 186

450 1H-NMR (H-NMR (500 MHz, CD3OD) δ ppm 8.58 (d, 1H, J = 2.0 Hz), 8.01(dd, J = 8.5 Hz, 2.5 Hz), 7.96 (d, 1H, J = 2.0 Hz), 7.87 (d, 1H, J = 5.5Hz), 7.00 (d, 1H, J = 8.5 Hz), 6.91 (d, 1H, J = 2.0 Hz), 6.03 (d, 1H, J= 5.5 Hz), 4.07-4.01 (m, 2H), 3.89-3.79 (m, 6H), 3.70-3.60 (m, 3H),3.57-3.51 (m, 2H), 3.39-3.35 (m, 4H), 2.61- 2.52 (m, 1H), 1.55-1.45 (m,1H), 1.35-1.28 (m, 1H). 187

450 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.92 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.11 (s, 1H), 6.80 (d, 1H, J = 1.6 Hz), 5.98(d, 1H, J = 5.6 Hz), 3.90-3.89 (m, 2H), 3.69-3.68 (m, 2H), 3.51 (s, 2H),3.45-3.40 (m, 2H), 3.35-3.30 (m, 2H), 2.90-2.85 (m, 1H), 2.73-2.71 (m,2H), 2.62-2.61 (m, 2H), 2.02-2.00 (m, 1H), 1.05 (d, 6H, J = 6.4 Hz),0.77-0.71 (m, 4H). 188

451 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.6 Hz), 6.62 (t, 1H, J = 5.6 Hz), 5.99 (d, 1H, J= 5.6 Hz), 3.60-3.50 (m, 4H), 3.50-3.40 (m, 4H), 3.11-3.05 (m, 2H),3.03-2.95 (m, 2H), 2.75-2.60 (m, 1H), 2.50- 2.44 (m, 2H), 2.25-2.20 (m,1H), 2.08-1.95 (m, 2H), 1.83-1.74 (m, 1H), 1.60-1.53 (m, 1H), 1.04 (t,3H, J = 7.2 Hz). 189

451 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (d, 1H, J = 1.2 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.88 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4Hz), 7.06 (d, 1H, J = 2.0 Hz), 6.62 (t, 1H, J = 5.6 Hz), 5.99 (d, 1H, J= 5.6 Hz), 3.60-3.52 (m, 4H), 3.48-3.42 (m, 4H), 3.42-3.38 (m, 1H),3.23-3.18 (m, 1H), 3.12-3.05 (m, 2H), 2.98- 2.90 (m, 2H), 2.30-2.20 (m,1H), 2.15-2.00 (m, 2H), 1.98-1.85 (m, 1H), 1.83-1.75 (m, 1H), 1.04 (t,3H, J = 7.6 Hz). 190

451 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 9.15- 9.00 (m, 1H), 8.90-8.80(m, 1H), 7.96 (d, 1H, J = 5.6 Hz), 7.95 (d, 1H, J = 1.2 Hz), 6.73 (d,1H, J = 1.2 Hz), 6.03 (d, 1H, J = 5.6 Hz), 4.00- 3.80 (m, 2H), 3.69-3.55(m, 2H), 3.58-3.50 (m, 2H), 3.50-3.40 (m, 2H), 3.40-3.25 (m, 3H),3.15-2.90 (m, 2H), 2.49 (s, 3H), 2.22-2.16 (m, 2H), 2.05-1.98 (m, 1H),1.98-1.90 (m, 2H), 0.79-0.73 (m, 4H). 191

451 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.96 (d, 1H, J = 5.6 Hz), 6.97 (d, 1H, J = 1.6 Hz), 6.02 (d, 1H, J = 5.6Hz), 3.95-3.92 (m, 2H), 3.73 (s, 2H), 3.73-3.68 (m, 2H), 3.58-3.54 (m,2H), 3.50-3.45 (m, 2H), 2.97-2.92 (m, 1H), 2.81 (d, 2H, J = 4.4 Hz),2.77 (d, 2H, J = 4.4 Hz), 2.02-1.98 (m, 1H), 1.07 (d, 6H, J = 6.8 Hz),0.79-0.73 (m, 4H). 192

453 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.91 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.10 (s, 1H), 6.77 (d, 1H, J = 1.6 Hz), 6.59(t, 1H, J = 5.2 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.64-3.62 (m, 2H),3.51-3.48 (m, 4H), 3.40-3.38 (m, 4H), 3.08-3.05 (m, 2H), 2.90-2.88 (m,1H), 2.61- 2.58 (m, 2H), 2.50-2.48 (m, 2H), 1.05-1.00 (m, 9H). 193

454 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (s, 1H), 7.95 (d, 1H, J= 5.6 Hz), 6.94 (s, 1H), 6.59 (t, 1H, J = 5.6 Hz), 6.02 (d, 1H, J = 5.6Hz), 3.73 (s, 2H), 3.53-3.50 (m, 4H), 3.46-3.44 (m, 4H), 3.10-3.06(quintet, 2H, J = 6.4 Hz), 2.93 (heptet, 1H, J = 6.8 Hz), 2.82-2.79 (m,2H), 2.77-2.72 (m, 2H), 1.07 (d, 6H, J 6.8 Hz), 1.03 (t, 3H, J = 7.2Hz). 194

456 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.83 (d, 1H, J = 5.6 Hz), 7.75(s, 2H), 7.63 (s, 1H), 6.52 (d, 1H, J = 1.6 Hz), 5.84 (d, 1H, J = 5.6Hz), 4.49-4.40 (m, 1H), 3.93-3.88 (m, 4H), 3.53-3.45 (m, 4H), 3.41-3.22(m, 2H), 3.10- 2.89 (m, 2H), 2.70-2.45 (m, 2H), 1.80-1.75 (m, 1H),1.06-1.03 (m, 2H), 0.89-0.80 (m, 2H). 195

457 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.4Hz), 7.06 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.45-4.35 (m,1H), 4.01-3.92 (m, 2H), 3.90-3.80 (m, 1H), 3.75-3.65 (m, 2H), 3.62- 3.52(m, 3H), 3.50-3.40 (m, 2H), 2.95-2.85 (m, 2H), 2.80-2.70 (m, 2H),2.55-2.51 (m, 2H), 2.15-2.00 (m, 1H), 1.50-1.40 (m, 1H), 1.37- 1.30 (m,1H). 196

457 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.33- 8.29 (br., 1H), 8.05(d, 1H, J = 1.6 Hz), 7.86 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.8 Hz),6.93 (d, 1H, J = 1.6 Hz), 6.85 (d, 2H, J = 8.8 Hz), 5.96 (d, 1H, J = 5.6Hz), 3.93-3.87 (m, 2H), 3.84-3.71 (m, 2H), 3.59-3.52 (m, 4H), 3.36-3.26(m, 4H), 3.04-2.97 (m, 2H), 2.74- 2.67 (m, 1H), 2.40-2.32 (m, 2H),2.04-2.00 (m, 1H), 1.82-1.77 (m, 1H), 1.61-1.55 (m, 1H), 0.78-0.74 (m,4H). 197

457 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.80- 8.60 (br., 1H), 8.05(d, 1H, J = 1.6 Hz), 7.87 (d, 1H, J = 5.6 Hz), 7.64 (d, 2H, J = 8.8 Hz),6.92 (d, 1H, J = 1.6 Hz), 6.49 (d, 2H, J = 8.8 Hz), 5.97 (d, 1H, J = 5.6Hz), 3.92-3.91 (m, 2H), 3.83 (dd, 4H, J = 12.8, 7.2 Hz), 3.71-3.70 (m,2H), 3.52-3.50 (m, 2H), 3.48-3.44 (m, 2H), 3.39-3.37 (m, 2H), 3.22 (t,2H, J = 7.2 Hz), 2.22 (t, 2H, J = 7.2 Hz), 2.03-2.02 (m, 1H), 0.79-0.75(m, 4H). 198

457 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.86 (s, 1H), 7.82 (d, 1H, J =5.2 Hz), 7.54 (d, 2H, J = 8.4 Hz), 6.64 (s, 1H), 6.60 (d, 2H, J = 8.4Hz), 5.83 (d, 1H, J = 5.2 Hz), 3.95-3.90 (m, 2H), 3.90-3.85 (m, 2H),3.60-3.53 (m, 4H), 3.53- 3.42 (m, 2H), 3.41-3.37 (m, 2H), 2.62-2.40(br., 4H), 2.30-2.25 (m, 2H), 1.80-1.77 (m, 1H), 1.05-1.03 (m, 2H),0.84-0.81 (m, 2H). 199

458 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.06 (s, 1H), 7.90-7.80 (m,1H), 7.63 (d, 2H, J = 8.0 Hz), 6.94 (d, 2H, J = 8.0 Hz), 6.85 (s, 1H),6.00-5.88 (m, 1H), 4.66 (br. s., 1H), 4.40-4.20 (m, 1H), 4.00-3.40 (m,4H), 3.26-3.12 (m, 2H), 3.10-3.02 (m, 4H), 2.98-2.76 (m, 5H), 2.74- 2.60(m, 3H), 1.40-1.20 (m, 3H). 200

458 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 8.14 (d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.2 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.25 (d,2H, J = 8.0 Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.2 Hz),3.94-3.90 (m, 4H), 3.79-3.62 (m, 4H), 3.60-3.47 (m, 3H), 3.10-3.07 (m,2H), 2.18-2.13 (m, 2H), 2.01-2.00 (m, 1H), 1.81- 1.69 (m, 4H), 1.06 (t,3H, J = 7.2 Hz), 0.80- 0.73 (m, 4H). 201

458 202

458 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.74 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.2 Hz), 4.00-3.80 (m,2H), 3.78-3.62 (m, 2H), 3.60-3.42 (m, 4H), 3.30-3.20 (m, 2H), 3.10- 2.90(m, 2H), 2.85-2.70 (m, 1H), 2.48-2.45 (m, 1H), 2.10-1.95 (m, 2H),1.90-1.70 (m, 2H), 1.68-1.40 (m, 2H), 1.15-0.90 (m, 3H), 0.80- 0.60 (m,4H). 203

458 204

458 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 1.8 Hz, 1H), 7.89(d, J = 5.5 Hz, 1H), 7.76- 7.67 (m, 2H), 7.35-7.22 (m, 2H), 7.01 (d, J =1.9 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 3.91 (s, 2H), 3.70 (s, 2H), 3.50(d, J = 27.8 Hz, 5H), 3.25 (dt, J = 9.4, 7.5 Hz, 1H), 2.98 (t, J = 8.4Hz, 1H), 2.83-2.62 (m, 2H), 2.44-2.31 (m, 1H), 2.26-2.11 (m, 0H), 2.01(tt, mJ = 7.7, 4.9 Hz, 1H), 1.81-1.68 (m, 1H), 1.05 (t, J = 6.3 Hz, 6H),0.76 (ddt, J = 9.8, 5.0, 2.5 Hz, 4H). 205

458 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.22 (s, 1H), 7.92 (d, 1H, J= 5.6 Hz), 7.82 (d, 2H, J = 8.0 Hz), 7.40-7.35 (m, 2H), 7.05 (s, 1H),5.98 (d, 1H, J = 5.6 Hz), 3.99-3.97 (m, 1H), 3.69- 3.38 (m, 6H),3.63-3.62 (m, 5H), 3.50-3.49 (m, 2H), 3.30-3.25 (m, 1H), 2.34-2.32 (m,3H), 2.22-2.20 (m, 1H), 1.25 (t, 3H, J = 7.2 Hz), 1.01-0.99 (m, 1H),0.48-0.45 (m, 2H), 0.15- 0.14 (m, 2H). 206

458 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.80 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J =8.;0 Hz), 7.05 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.00-3.85(m, 2H), 3.80-3.65 (m, 2H), 3.60-3.40 (m, 6H), 3.20-2.90 (m, 4H), 2.10-1.80 (m, 5H), 1.70-1.50 (m, 1H), 1.30-1.10 (m, 3H), 0.80-0.60 (m, 4H).207

458 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.80 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.0Hz), 7.05 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.00-3.85 (m,2H), 3.80-3.65 (m, 2H), 3.60-3.40 (m, 6H), 3.20-2.90 (m, 4H), 2.10- 1.80(m, 5H), 1.70-1.50 (m, 1H), 1.30-1.10 (m, 3H), 0.80-0.60 (m, 4H). 208

458 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (s, 1H), 7.90 (d, 1H, J= 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 7.01 (s,1H), 5.97 (d, 1H, J = 5.6 Hz), 3.90-3.88 (m, 2H), 3.68-3.66 (m, 2H),3.54-3.50 (m, 2H), 3.49- 3.44 (m, 2H), 3.31-3.27 (m, 1H), 2.93-2.89 (m,1H), 2.68-2.62 (m, 2H), 2.50-2.48 (m, 1H), 2.46-2.42 (m, 2H), 2.26-2.18(m, 1H), 1.76- 1.72 (m, 2H), 1.18-1.12 (m, 1H), 1.09-1.03 (m, 6H),0.99-0.95 (m, 1H), 0.60-0.56 (m, 1H). 209

459 210

459 211

459 212

459 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.06 (s, 1H), 7.87 (d, 1H, J= 5.2 Hz), 7.65 (d, 2H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.8 Hz), 6.93 (s,1H), 5.95 (d, 1H, J = 5.6 Hz), 3.68-3.36 (m, 9H), 3.17-3.15 (m, 4H),2.50-2.47 (m, 4H), 2.23- 2.11 (m, 7H), 1.93-1.90 (m, 1H), 1.78-1.76 (m,1H). 213

459 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.27 (br. s., 1H), 8.07 (d,1H, J = 1.2 Hz), 7.88 (d, 1H, J = 5.2 Hz), 7.66 (d, 2H, J = 8.4 Hz),6.97- 6.95 (m, 3H), 5.96 (d, 1H, J = 5.6 Hz), 3.92- 3.70 (m, 6H),3.52-3.45 (m, 6H), 3.17-3.15 (m, 4H), 2.41-2.36 (q, 2H, J = 7.2 Hz),2.03-2.00 (m, 1H), 1.06-1.02 (m, 3H), 0.78-0.72 (m, 4H). 214

460 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 8.0 Hz), 7.36 (d, 2H, J = 8.0Hz), 7.05 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.2 Hz), 4.49-4.47 (m,1H), 3.96-3.93 (m, 3H), 3.70-3.64 (m, 3H), 3.54-3.47 (m, 4H), 2.94- 2.91(m, 1H), 2.80-2.77 (m, 1H), 2.50-2.35 (m, 2H), 2.08-2.00 (m, 2H),1.91-1.88 (m, 1H), 1.02 (t, 3H, J = 7.2 Hz), 0.78-0.72 (m, 4H). 215

460 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0Hz), 7.03 (s, 1H), 6.00 (d, 1H, J = 5.6 Hz), 3.77- 3.68 (m, 2H),3.66-3.58 (m, 2H), 3.56-3.44 (m, 4H), 3.06-2.94 (m, 2H), 2.42 (s, 3H),2.40-2.29 (m, 1H), 2.36 (q, 2H, J = 7.2 Hz), 2.08-1.90 (m, 2H),1.83-1.72 (m, 2H), 1.72-1.58 (m, 2H), 1.03 (t, 3H, J = 7.2 Hz). 216

460 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.75 (d, 2H, J = 8.8 Hz), 6.99 (d, 1H, J = 1.6Hz), 6.96 (d, 2H, J = 8.8 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.07-5.03 (m,1H), 3.95-3.90 (m, 2H), 3.73-3.69 (m, 2H), 3.55-3.50 (m, 2H), 3.50- 3.45(m, 2H), 3.35-3.12 (m, 4H), 2.88-2.82 (m, 2H), 2.42-2.33 (m, 1H),2.05-2.03 (m, 1H), 2.00-1.97 (m, 1H), 1.14 (t, 3H, J = 7.2 Hz),0.79-0.75 (m, 4H). 217

460 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ 8.12 (d, 1H, J = 2.0 Hz), 7.89(d, 1H, J = 5.2 Hz), 7.76 (d, 2H, J = 8.8 Hz), 7.01 (d, 2H, J = 8.8 Hz),6.99 (s, 1H), 5.97 (d, 1H, J = 5.2 Hz), 4.17 (d, 2H, J = 5.2 Hz),4.05-3.99 (m, 2H), 3.95-3.90 (m, 2H), 3.90-3.78 (m, 2H), 3.74-3.65 (m,2H), 3.58-3.48 (m, 2H), 3.47-3.42 (m, 2H), 3.20- 3.10 (m, 1H), 3.10-3.04(m, 2H), 2.04-2.0 (m, 1H), 1.06 (t, 3H, J = 6.8 Hz), 0.78-0.74 (m, 4H).218

460 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (s, 1H), 8.11 (d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 6.99 (d,1H, J = 1.6 Hz), 6.97 (d, 2H, J = 8.4 Hz), 5.98 (d, 1H, J = 5.6 Hz),4.05-3.93 (m, 2H), 3.87-3.85 (m, 2H), 3.70-3.66 (m, 4H), 3.48-3.45 (m,4H), 2.93-2.89 (m, 1H), 2.85-2.78 (m, 1H), 2.11- 2.07 (m, 1H), 2.03-1.97(m, 2H), 0.94 (t, 3H, J = 7.2 Hz), 0.78-0.75 (m, 4H). 219

460 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 10.50- 9.84 (m, 1H), 8.28 (d,1H, J = 1.6 Hz), 7.92 (d, 1H, J = 5.6 Hz), 7.90 (d, 2H, J = 8.4 Hz),7.53 (d, 2H, J = 8.4 Hz), 7.11 (d, 1H, J = 2.0 Hz), 6.76 (s, 1H), 5.99(d, 1H, J = 5.6 Hz), 4.66- 4.22 (m, 2H), 4.27-4.11 (m, 2H), 3.95-3.90(m, 2H), 3.74-3.68 (m, 2H), 3.55-3.50 (m, 5H), 2.06-1.99 (m, 1H),1.20-1.16 (m, 6H), 0.79- 0.75 (m, 4H). 220

460 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.10 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 6.97 (d, 1H, J = 1.6Hz), 6.86 (d, 2H, J = 8.4 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.75-4.74 (m,1H), 3.91-3.90 (m, 1H), 3.69 (dd, 4H, J = 7.6, 6.0 Hz), 3.53-3.48 (m,2H), 3.46-3.41 (m, 2H), 2.93-2.89 (m, 2H), 2.32-2.29 (m, 2H), 2.02-2.01(m, 1H), 0.87 (d, 6H, J = 6.0 Hz), 0.78-0.72 (m, 4H). 221

460 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.13 (s, 1H),7.98-7.96 (dd, 1H, J =8.8, 1.6 Hz), 7.88 (d, 1H, J = 5.2 Hz), 7.01 (s,1H), 6.88 (d, 1H, J = 5.2 Hz), 3.92 (br. s., 2H), 3.70 (br. s., 2H),3.52-3.46 (m, 8H), 3.33 (br. s., 2H), 2.44-2.36 (m, 2H), 2.04-1.99 (m,1H), 1.05 (t, 3H, J = 6.4 Hz), 0.78-0.74 (m, 4H). 222

460 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.29 (s, 1H), 8.16 (s, 1H),7.90 (d, 1H, J = 4.8 Hz), 7.76 (d, 1H, J = 8.8 Hz), 7.36 (d, 1H, J = 8.8Hz), 7.08 (s, 1H), 5.97 (d, 1H, J = 4.8 Hz), 3.94-3.91 (m, 2H),3.73-3.68 (m, 2H), 3.56- 3.52 (m, 2H), 3.49-3.45 (m, 2H), 3.27-3.19 (m,4H), 2.50-2.40 (m, 4H), 2.39 (q, 2H, J = 7.2 Hz), 2.03-1.97 (m, 1H),1.04 (t, 3H, J = 7.2 Hz), 0.80-0.73 (m, 4H). 223

461 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 1.6 Hz),7.87 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.4 Hz), 6.97 (s, 1H), 6.95(d, 2H, J = 8.4 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.74-3.69 (m, 4H),3.59-3.57 (m, 8H), 3.17-3.15 (m, 4H), 2.90-2.80 (m, 1H), 2.37 (q, 2H, J= 7.2 Hz), 1.04 (d, 6H, , J = 7.2 Hz), 1.03 (t, 3H, J = 7.2 Hz). 224

461 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0Hz), 6.99 (d, 1H, J = 1.6 Hz), 6.61 (t, 1H, J = 5.6 Hz), 5.97 (d, 1H, J= 5.6 Hz), 3.60-3.47 (m, 4H), 3.46-3.38 (m, 4H), 3.30-3.20 (m, 1H),3.12-3.03 (m, 2H), 3.02-2.94 (m, 1H), 2.80- 2.64 (m, 2H), 2.49-2.44 (m,1H), 2.43-2.35 (m, 1H), 2.26-2.15 (m, 1H), 1.80-1.70 (m, 1H), 1.10-1.00(m, 9H). 225

461 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0Hz), 6.99 (d, 1H, J = 1.6 Hz), 6.61 (t, 1H, J = 5.6 Hz), 5.98 (d, 1H, J5.6 Hz), 3.52-3.51 (m, 4H), 3.44-3.43 (m, 4H), 3.31-3.25 (m, 1H),3.12-3.05 (m, 2H), 3.01-2.97 (m, 1H), 2.74- 2.68 (m, 2H), 2.47-2.38 (m,2H), 2.23-2.19 (m, 1H), 1.78-1.73 (m, 1H), 1.07-1.01 (m, 9H). 226

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.73 (d, 2H, J = 8.04 Hz), 7.30 (d, 2H, J =8.4 Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.2 Hz), 5.05-4.88(m, 1H), 3.93-3.90 (m, 2H), 3.74-3.73 (m, 2H), 3.48-3.28 (m, 4H), 2.93-2.92 (m, 1H), 2.68-2.65 (m, 2H), 2.46-2.42 (m, 3H), 2.24-2.20 (m, 2H),1.76-1.75 (m, 1H), 1.52-1.08 (m, 1H), 1.06 (t, 3H, J = 6.8 Hz). 227

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (s, 1H), 8.17 (s, 1H),7.91 (s, 1H, J = 5.2 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0Hz), 7.05 (s, 1H), 5.99 (d, 1H, J = 5.2 Hz), 5.09-4.83 (m, 1H),4.01-3.82 (m, 3H), 3.79- 3.68 (m, 3H), 3.62-3.58 (m, 1H), 3.53-3.41 (m,3H), 3.12 (t, 1H, J = 8.4 Hz), 2.90-2.80 (m, 2H), 272-2.59 (m, 3H),1.89-1.78 (m, 1H), 1.62-1.50 (m, 1H), 1.11 (t, 3H, J = 7.2 Hz). 228

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 2.0 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 2.0 Hz), 5.97 (d, 1H, J = 5.2 Hz), 5.30-5.00 (m,1H), 4.00-3.83 (m, 2H), 3.80-3.62 (m, 2H), 3.57-3.50 (m, 2H), 3.49- 3.42(m, 2H), 3.40-3.35 (m, 2H), 3.30-3.20 (m, 2H), 3.18-3.00 (m, 1H),2.80-2.60 (m, 1H), 2.35-2.20 (m, 1H), 2.10-1.95 (m, 1H), 1.06 (t, 3H, J= 7.2 Hz), 0.80-0.60 (m, 4H). 229

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.21 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.44 (d, 2H, J = 8.4Hz), 7.06 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.72-3.60 (m,2H), 3.60-3.50 (m, 2H), 3.50-3.38 (m, 4H), 3.37-3.34 (m, 1H), 3.08- 3.05(m, 1H), 3.04-2.97 (m, 2H), 2.70-2.61 (m, 1H), 2.27-2.20 (m, 2H),2.20-2.08 (m, 4H), 2.03-1.98 (m, 1H), 1.95-1.90 (m, 1H), 1.85- 1.80 (m,1H), 1.80-1.74 (m, 1H), 1.59-1.54 (m, 1H). 230

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.09 (q, 2H, J= 7.2 Hz), 3.66-3.55 (m, 4H), 3.49-3.41 (m, 4H), 3.03-2.93 (m, 2H), 2.35(q, 2H, J = 7.2 Hz), 2.33-2.29 (m, 1H), 2.00-1.90 (m, 2H), 1.80-1.72 (m,2H), 1.72- 1.59 (m, 2H), 1.22 (t, 3H, J = 7.2 Hz), 1.02 (t, 3H, J = 7.2Hz). 231

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.2 Hz),7.88 (d, 1H, NJ = 5.2 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J =8.0 Hz), 6.98 (d, 1H, J = 1.2 Hz), 5.95 (d, 1H, J = 5.2 Hz), 4.07 (q,2H, J = 6.8 Hz), 3.65-3.55 (m, 4H), 3.50-3.42 (m, 4H), 3.30-3.20 (m,1H), 2.98 (t, 1H, J = 8.4 Hz), 2.78-2.74 (m, 1H), 2.70-2.65 (m, 1H),2.48 (t, 1H, J = 8.4 Hz), 2.45-2.37 (m, 1H), 2.25-2.10 (m, 1H), 1.80-1.65 (m, 1H), 1.20 (t, 3H, J = 6.8 Hz), 1.10- 1.00 (m, 6H). 232

463 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.7 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H),6.98 (d, J = 1.8 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 3.64 (s, 3H), 3.60(t, J = 5.1 Hz, 4H), 3.45 (t, J = 5.1 Hz, 4H), 2.88 (d, J = 10.9 Hz,3H), 2.70 (p, J = 6.6 Hz, 1H), 2.21 (t, J = 11.2 Hz, 2H), 1.76 (d, J =12.4 Hz, 2H), 1.61 (tt, J = 12.2, 6.3 Hz, 2H), 0.99 (d, J = 6.5 Hz, 6H).233

478 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 8.68 (s, 1H), 7.92 (s, 1H),7.85 (d, 1H, J = 5.6 Hz), 7.62 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0Hz), 6.68 (s, 1H), 5.85 (d, 1H, J = 5.6 Hz), 4.20 (q, 2H, J = 7.2 Hz),3.77-3.71 (m, 4H), 3.60-3.55 (m, 1H), 3.54-3.50 (m, 1H), 3.49- 3.41 (m,4H), 3.40-3.38 (m, 1H), 3.21-3.28 (m, 1H), 3.18-3.11 (m, 1H), 3.05-2.94(m, 1H), 2.40-2.50 (m, 1H), 2.20-2.10 (m, 1H), 1.36 (d, 6H, J = 6.4 Hz),1.31 (t, 3H, J = 7.2 Hz). 234

464 235

463 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.2 Hz),8.15 (s, 1H), 7.89 (d, 1H, J = 5.2 Hz), 7.80 (d, 2H, J = 8.0 Hz), 7.61(d, 2H, J = 8.0 Hz), 7.02 (d, 1H, J = 1.6 Hz), 6.60 (t, 1H, J = 5.6 Hz),6.00-5.97 (m, 2H), 3.72-3.70 (m, 2H), 3.52-3.51 (m, 4H), 3.41-3.44 (m,6H), 3.11-3.04 (m, 2H), 2.66-2.50 (m, 1H), 1.03 (t, 3H, J = 7.6 Hz),0.96 (d, 6H, J = 6.0 Hz). 236

464 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.10 (d, 1H, J = 2.0 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 6.97 (d, 1H, J = 2.0Hz), 6.86 (d, 2H, J = 8.4 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.75-4.74 (m,1H), 4.08 (q, 2H, J = 7.2 Hz), 3.71-3.68 (m, 2H), 3.59-3.58 (m, 4H),3.43-3.40 (m, 4H), 3.35-3.30 (m, 1H), 2.95- 2.90 (m, 2H), 1.21 (d, 3H, J= 7.2 Hz), 0.88 (d, 2H, J = 6.4 Hz). 237

464 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (s, 1H), 7.87 (d, 1H, J= 5.6 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.00-6.90 (m, 3H), 5.95 (d, 1H, J =5.6 Hz), 4.00-3.85 (m, 2H), 3.75-3.60 (m, 2H), 3.58-3.48 (m, 2H),3.47-3.40 (m, 2H), 3.20- 3.00 (m, 4H), 2.48-2.40 (m, 4H), 2.10-1.90 (m,1H), 0.80-0.65 (m, 4H). 238

466 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 4.2 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.0Hz), 7.05 (s, 1H), 5.96 (d, 1H, J = 4.2 Hz), 3.92 (br. s., 2H), 3.70(br. s., 2H), 3.54 (br. s., 2H), 3.47 (br. s., 2H), 3.26-3.08 (m, 3H),3.01-2.98 (m, 1H), 2.89-2.77 (m, 1H), 2.65-2.59 (m, 1H), 2.05-1.96 (m,2H), 1.79-1.75 (m, 1H), 0.77- 0.74 (m, 4H). 239

467 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.94 (d, 1H, J = 5.6 Hz),7.89 (d, 1H, J = 1.2 Hz), 6.83 (d, 1H, J = 1.2 Hz), 6.73 (d, 2H, J =12.8 Hz), 3.95-3.90 (m, 2H), 3.70-3.65 (m, 2H), 3.57- 3.52 (m, 2H),3.47-3.43 (m, 2H), 3.15-3.12 (m, 4H), 2.82-2.79 (m, 4H), 2.03-1.99 (m,1H), 0.78-0.73 (m, 4H). 240

467 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (d, 1H, J = 1.6 Hz),7.85 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.4Hz), 6.91 (d, 1H, J = 1.6 Hz), 6.60 (t, 1H, J = 5.2 Hz), 5.96 (d, 1H, J= 5.2 Hz), 3.60-3.46 (m, 4H), 3.44-3.36 (m, 4H), 3.20-3.12 (m, 4H), 3.06(quintet, 2H, J = 6.8 Hz), 2.48-2.40 (m, 4H), 1.02 (d, 3H, J = 7.2 Hz).241

471 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.85 (d, 1H, J = 2.0 Hz), 7.82(d, 1H, J = 5.2 Hz), 7.52 (d, 2H, J = 8.4 Hz), 6.63 (d, 1H, J = 2.0 Hz),6.50 (d, 2H, J = 8.8 Hz), 5.83 (d, 1H, J = 5.2 Hz), 4.07-4.02 (m, 4H),3.95-3.92 (m, 2H), 3.90-3.85 (m, 2H), 3.80-3.75 (m, 4H), 3.56- 3.52 (m,2H), 3.48-3.44 (m, 2H), 2.79 (q, 2H, J = 7.2 Hz), 1.80-1.75 (m, 1H),1.16 (t, 3H, J = 7.2 Hz), 1.06-1.03 (m, 2H), 0.84-0.81 (m, 2H). 242

471 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.01 (d, 1H, J = 1.6 Hz),7.85 (d, 1H, J = 5.6 Hz), 7.57 (d, 2H, J = 8.8 Hz), 6.88 (d, 1H, J = 1.6Hz), 6.59 (d, 2H, J = 8.8 Hz), 5.95 (d, 1H, J = 5.6 Hz), 4.35-4.30 (m,1H), 3.95-3.85 (m, 2H), 3.75-3.65 (m, 2H), 3.60-.40 (m, 5H), 3.16-3.14(m, 1H), 2.84-2.82 (m, 1H), 2.45-2.35 (m, 4H), 2.05-1.95 (m, 1H), 1.80(q, 2H, J = 7.2 Hz), 0.93 (t, 3H, J = 7.2 Hz), 0.80-0.71 (m, 4H). 243

471 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (br s., 1H), 8.06 (d,1H, J = 1.6 Hz), 7.87 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.8 Hz),6.97 (d, 2H, J = 8.8 Hz), 6.93 (d, 1H, J = 1.6 Hz), 5.95 (d, 1H, J = 5.2Hz), 3.96-3.90 (m, 2H), 3.82- 3.64 (m, 8H), 3.08-3.00 (m, 2H), 2.78-2.71(m, 1H), 2.41 (t, 1H, J = 10.4 Hz), 2.27-2.21 (m, 1H), 2.11-2.00 (m,3H), 1.86-1.80 (m, 1H), 1.76-1.66 (m, 2H), 1.43-1.32 (m, 1H), 0.78- 0.74(m, 4H). 244

471 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.37 (s, 1H), 8.02 (d, 1H, J= 2.0 Hz), 7.86 (d, 1H, J = 5.2 Hz), 7.63 (d, 2H, J = 8.8 Hz), 6.90 (d,1H, J = 2.0 Hz), 6.54 (d, 2H, J = 8.8 Hz), 5.96 (d, 1H, J = 5.60 Hz),3.92-3.91 (m, 2H), 3.71-3.70 (m, 2H), 3.52-3.49 (m, 2H), 3.47-3.44 (m,2H), 3.35 (t, 2H, J = 7.2 Hz), 3.31-3.30 (m, 1H), 3.24-3.20 (m, 2H),3.16 (t, 2H, J = 7.2 Hz), 3.01-3.00 (m, 2H), 205-1.97 (m, 3H), 1.88-1.85 (m, 2H), 0.78-0.74 (m, 4H). 245

472 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 4.55-4.52 (m,1H), 3.93-3.91 (m, 3H), 3.70 (br. s., 2H), 3.53-3.47 (m, 4H), 3.15-3.09(m, 1H), 2.78-2.73 (m, 1H), 2.61-2.50 (m, 1H), 2.04-2.00 (m, 4H),1.82-1.76 (m, 2H), 1.63- 1.59 (m, 1H), 1.47-1.43 (m, 1H), 0.77-0.74 (m,4H). 246

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J = 8.0Hz), 7.01 (d, 1H, J = 1.2 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.95-3.90 (m,2H), 3.72-3.68 (m, 2H), 3.55-3.50 (m, 2H), 3.47-3.42 (m, 2H), 2.89- 2.85(m, 2H), 2.73-2.67 (m, 1H), 2.46-2.42 (m, 1H), 2.21 (t, 2H, J = 3.2 Hz),2.05-1.98 (m, 1H), 1.77-1.74 (m, 2H), 1.67-1.55 (m, 2H), 0.98 (d, 6H, J= 6.8 Hz), 0.80-0.71 (m, 4H). 247

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.2 Hz), 3.93-3.92 (m,2H), 3.71-3.70 (m, 2H), 3.54-3.50 (m, 2H), 3.49-3.43 (m, 2H), 2.81- 2.79(m, 2H), 2.74-2.10 (m, 1H), 2.67-2.63 (m, 1H), 2.19-2.14 (m, 2H),2.04-2.00 (m, 1H), 1.81-1.80 (m, 1H), 1.71-1.70 (m, 1H), 1.59- 1.50 (m,1H), 1.45-1.30 (m, 1H), 0.98-0.92 (m, 6H), 0.79-0.74 (m, 4H). 248

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.2 Hz), 3.93-3.92 (m,2H), 3.71-3.70 (m, 2H), 3.54-3.50 (m, 2H), 3.49-3.43 (m, 2H), 2.81- 2.79(m, 2H), 2.74-2.10 (m, 1H), 2.67-2.63 (m, 1H), 2.19-2.14 (m, 2H),2.04-2.00 (m, 1H), 1.81-1.80 (m, 1H, 1.71-1.70 (m, 1H), 1.59- 1.50 (m,1H), 1.45-1.30 (m, 1H), 0.98-0.92 (m, 6H), 0.79-0.74 (m, 4H). 249

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.70-3.64 (m,2H), 3.60-3.54 (m, 2H), 3.45-3.40 (m, 4H), 3.40-3.38 (m, 1H), 3.30- 3.28(m, 1H), 2.98 (t, 1H, J = 8.0 Hz), 2.75- 2.71 (m, 1H), 2.70-2.67 (m,1H), 2.50-2.45 (m, 1H), 2.44-2.38 (m, 1H), 2.25-2.20 (m, 3H), 2.19-2.11(m, 2H), 1.90-1.92 (m, 1H), 1.74- 1.77 (m, 2H), 1.05 (t, 6H, J = 6.4Hz). 250

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 3.69-3.66 (m,2H), 3.57-3.54 (m, 2H), 3.46-3.42 (m, 4H), 3.40-3.33 (m, 2H), 3.10- 3.00(m, 2H), 2.58-2.50 (m, 2H), 2.19 (q, 2H, J= 7.2 Hz), 2.20-2.11 (m, 4H),1.98-1.86 (m, 1H), 1.83-1.73 (m, 4H), 1.72-1.69 (m, 1H), 1.08 (t, 3H, J= 7.2 Hz). 251

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (s, 1H), 7.89 (d, 1H, J= 5.2 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.4 Hz), 7.02 (s,1H), 5.97 (d, 1H, J = 5.2 Hz), 3.86-3.82 (m, 1H), 3.80-3.71 (m, 2H),3.68-3.61 (m, 2H), 3.47- 3.43 (m, 2H), 3.31-3.26 (m, 3H), 2.93-2.89 (m,1H), 2.68-2.61 (m, 2H), 2.47-2.40 (m, 2H), 2.24-2.20 (m, 1H), 1.78-1.72(m, 2H), 1.19 (s, 3H), 1.05 (t, 3H, J = 6.8 Hz), 0.97 (s, 3H), 0.96-0.93(m, 1H), 0.68-0.65 (m, 1H). 252

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.31 (s, 1H), 8.14 (d, 1H, J= 1.6 Hz), 7.88 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.25 (d,2H, J = 8.0 Hz), 6.94 (d, 1H, J = 1.6 Hz), 5.95 (d, 1H, J = 5.6 Hz),4.65-4.64 (m, 1H), 4.20-4.16 (m, 1H), 3.94-3.87 (m, 2H), 3.75-3.63 (m,1H), 3.25-3.23 (m, 2H), 3.01-2.98 (m, 2H), 2.54- 2.49 (m, 1H), 2.38 (q,2H, J = 7.2 Hz), 2.02- 1.96 (m, 3H), 1.77-1.70 (m, 2H), 1.70-1.64 (m,2H), 1.41-1.23 (m, 2H), 1.02 (t, 2H, J = 7.2 Hz), 0.81-0.71 (m, 4H). 253

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (s, 1H), 7.87 (d, 1H, J= 5.6 Hz), 7.73 (d, 2H, J = 7.2 Hz), 7.33 (d, 2H, J = 7.2 Hz), 6.95 (s,1H), 5.94 (d, 1H, J = 5.2 Hz), 4.68-4.62 (m, 1H), 4.22-4.14 (m, 1H),3.97-3.84 (m, 2H), 3.74- 3.50 (m, 2H), 3.30-3.00 (m, 4H), 2.47-2.40 (m,2H), 2.35-2.25 (m, 1H), 2.05-1.95 (m, 1H), 1.90-1.83 (m, 1H), 1.45-1.10(m, 3H), 1.00 (m, 6H), 0.82-0.70 (m, 4H). 254

472 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.87 (d, 1H, J = 5.6 Hz), 7.70 (d, 2H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.0Hz), 6.94 (d, 1H, J = 1.6 Hz), 5.94 (d, 1H, J = 5.6 Hz), 4.65-4.64 (m,1H), 4.19-4.16 (m, 1H), 3.95-3.92 (m, 2H), 3.30-3.24 (m, 3H), 2.99- 2.97(m, 1H), 2.72-2.71 (m, 2H), 2.49-2.39 (m, 3H), 2.23-2.22 (m, 1H),2.00-1.97 (m, 1H), 1.78-1.75 (m, 1H), 1.43-1.38 (m, 3H), 1.07- 1.03 (s,6H), 0.75-0.74 (m, 4H). 255

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.93 (d, 1H, J = 5.6 Hz),7.87 (s, 1H), 7.41 (d, 1H, J = 7.2 Hz), 7.20 (s, 1H), 7.17 (d, 1H, J =7.2 Hz), 6.77 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 4.00-3.80(m, 2H), 3.75-3.60 (m, 2H), 3.60-3.50 (m, 2H), 3.50-3.40 (m, 2H), 3.35-3.30 (m, 2H), 3.20-2.99 (m, 2H), 2.80-2.60 (m, 2H), 2.43 (s, 3H),2.33-2.18 (m, 1H), 2.06-1.94 (m, 1H), 1.89-1.70 (m, 1H), 1.21-0.92 (m,6H), 0.83-0.71 (m, 4H). 256

472 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.94 (d, 1H, J = 5.6 Hz),7.89 (d, 1H, J = 1.6 Hz), 7.48 (d, 1H, J = 8.0 Hz), 7.28 (s, 1H), 7.23(d, 1H, J = 8.0 Hz), 6.78 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz),3.95-3.90 (m, 2H), 3.75-3.70 (m, 2H), 3.60-3.53 (m, 2H), 3.50-3.40 (m,2H), 3.35-3.30 (m, 4H), 3.30-3.00 (m, 1H), 2.45 (s, 3H), 2.45-2.25 (m,2H), 2.20-1.91 (m, 2H), 1.30-0.14 (m, 6H), 0.83-0.71 (m, 4H). 257

473 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.8 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.30 (t, J = 7.8 Hz, 2H),7.02 (d, J = 1.8 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 3.92 (s, 1H), 3.70(s, 2H), 3.60-3.43 (m, 6H), 2.91 (d, J = 11.4 Hz, 1H), 2.74 (q, J = 6.7Hz, 1H), 2.20-2.06 (m, 1H), 2.01 (tt, J = 7.9, 3.8 Hz, 1H), 1.67 (dt, J= 25.8, 13.4 Hz, 3H), 1.47 (t, J = 11.7 Hz, 1H), 0.93 (d, J = 7.1 Hz,4H), 0.83-0.66 (m, 8H). 258

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (s, 1H), 7.92 (d, 1H, J= 5.2 Hz), 7.86 (d, 2H, J = 7.6 Hz), 7.46 (d, 2H, J = 7.6 Hz), 7.11 (s,1H), 6.00 (d, 1H, J = 5.2 Hz), 4.10-3.90 (m, 2H), 2.80-2.57 (m, 2H),3.70-3.57 (m, 2H), 3.55- 3.48 (m, 2H), 3.40-3.35 (m, 2H), 3.25-3.20 (m,1H), 3.10-3.00 (m, 1H), 2.95-2.90 (m, 1H), 2.81-2.74 (m, 1H), 2.20-2.08(m, 2H), 2.05- 1.97 (m, 2H), 1.93-1.78 (m, 1H), 1.74-1.72 (m, 1H),1.50-1.43 (m, 1H), 1.40-1.28 (m, 1H). 259

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.81 (d, 2H, J = 8.0 Hz, 7.32 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.2 Hz), 3.91 (br. s,2H), 3.70-3.65 (m, 2H), 3.55- 3.50 (m, 4H), 3.48-3.45 (m, 2H), 3.14 (s,2H), 2.76 (t, 2H, J = 5.2 Hz), 2.44 (q, 2H, J = 7.6 Hz), 1.99 (quintet,1H, J = 5.2 Hz), 1.04 (t, 3H, J = 7.6 Hz), 0.77-0.72 (m, 4H). 260

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.08 (d, 1H, J = 1.2 Hz),7.87 (d, 1H, J = 5.2 Hz), 7.67 (d, 2H, J = 8.8 Hz), 7.01 (d, 2H, J = 8.8Hz), 6.95 (d, 1H, J = 1.2 Hz), 5.95 (d, 1H, J = 5.2 Hz), 4.40-4.30 (m,4H), 4.00-3.80 (m, 2H), 3.78-3.62 (m, 2H), 3.58-3.50 (m, 2H), 3.48- 3.42(m, 2H), 3.26-3.20 (m, 2H), 3.05-2.95 (m, 2H), 2.80-2.75 (m, 2H),2.10-1.90 (m, 1H), 0.80-0.60 (m, 4H). 261

473 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.88 (s, 1H), 7.83 (d, 1H, J =5.2 Hz), 7.56 (d, 2H, J = 8.8 Hz), 6.98 (d, 2H, J = 8.4 Hz), 6.63 (s,1H), 5.83 (d, 1H, J = 5.2 Hz), 3.94-3.89 (m, 4H), 3.55-3.47 (m, 4H),3.31-3.28 (m, 4H), 2.80- 2.74 (m, 5H), 1.82-1.75 (m, 1H), 1.15 (d, 6H, J= 5.2 Hz), 1.06-1.03 (m, 2H), 0.85-0.81 (m, 2H). 262

473 1H-NMR (H-NMR (500 MHz, DMSO-d6) δ ppm 8.06 (s, 1H), 7.86 (d, 1H, J= 5.5 Hz), 7.66-7.64 (m, 2H), 6.96-6.92 (m, 3H), 5.94 (d, 1H, J = 5.0Hz), 3.68-3.66 (m, 2H), 3.56-3.54 (m, 2H), 3.45-3.39 (m, 6H), 3.32-3.30(m, 2H), 3.18- 3.14 (m, 4H), 2.43-2.34 (m, 2H), 2.24-2.11 (m, 5H),1.94-1.89 (m, 1H), 1.79-1.75 (m, 1H), 1.04 (t, 3H, J = 7.0 Hz). 263

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.04 (d, 1H, J = 1.2 Hz),7.84 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.8Hz), 6.94 (s, 1H), 5.93 (d, 1H, , J = 5.2 Hz), 4.53- 4.10 (m, 3H),3.72-3.39 (m, 6H), 3.29-2.96 (m, 6H), 2.36 (q, 2H, J = 7.2 Hz),2.07-1.97 (m, 1H), 1.08-0.98 (m, 3H), 1.03 (t, 3H, J = 7.2 Hz),0.79-0.74 (m, 4H). 264

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.64 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.4Hz), 6.93 (s, 1H), 5.95 (d, 1H, J = 5.6 Hz), 3.92- 3.91 (m, 2H),3.70-3.69 (m, 2H), 3.51-3.45 (m, 6H), 2.88-2.80 (m, 1H), 2.80-2.72 (m,2H), 2.47 (q, 2H, J = 7.2 Hz), 2.34-2.32 (m, 2H), 2.02-2.01 (m, 1H),1.05 (d, 3H, J = 5.2 Hz), 0.98 (t, 3H, J = 7.2 Hz), 0.77-0.74 (m, 4H).265

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (d, 1H, J = 1.2 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.63 (d, 2H, J = 8.8 Hz), 6.94 (d, 2H, J = 8.8Hz), 6.93 (s, 1H), 5.94 (d, 1H, J = 6.0 Hz), 3.91- 3.90 (m, 2H),3.70-3.69 (m, 2H), 3.49-3.45 (m, 6H), 2.88-2.76 (m, 3H), 2.49-2.47 (m,2H), 2.33-2.28 (m, 2H), 2.01-1.99 (m, 1H), 1.05 (d, 3H, J = 4.8 Hz),0.98 (t, 3H, J = 7.2 Hz), 0.77- 0.73 (m, 4H). 266

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.47 (d, 1H, J = 1.6 Hz),8.27 (d, 1H, J = 1.2 Hz), 7.94- 7.90 (m, 2H), 7.67 (d, 1H, J = 6.8 Hz),7.18 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 3.97- 3.94 (m, 2H),3.73-3.69 (m, 2H), 3.60-3.55 (m, 2H), 3.54-3.49 (m, 2H), 3.34-3.28 (m,2H), 3.01-2.90 (m, 2H), 2.88-2.81 (m, 2H), 2.06- 2.00 (m, 2H), 1.99-1.91(m, 2H), 1.23-1.15 (m, 7H), 0.79-0.73 (m, 4H). 267

473 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.97 (s, 1H), 8.27 (s, 1H),8.11 (dd, 1H, J = 8.0, 2.0 Hz), 7.91 (d, 1H, J = 5.6 Hz), 7.29 (d, 1H, J= 8.0 Hz),k 7.14 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz),3.92-3.91 (m, 2H), 3.69-3.68 (m, 2H), 3.60-3.50 (m, 2H), 3.50-3.40 (m,2H), 2.97-2.81 (m, 2H), 2.75-2.61 (m, 2H), 2.33- 2.08 (m, 2H), 2.06-2.02(m, 1H), 1.90-1.80 (m, 2H), 1.79-1.61 (m, 2H), 1.08-1.00 (m, 6H),0.77-0.74 (m, 4H). 268

474 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.86 (d, 1H, J = 1.6 Hz), 7.82(d, 1H, J = 5.2 Hz), 7.56 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.8 Hz),6.65 (d, 1H, J = 1.6 Hz), 5.82 (d, 1H, J = 5.2 Hz), 4.38 (quintet, 1H, J= 3.6 Hz), 3.99-3.90 (m, 2H), 3.90-3.75 (m, 2H), 3.60-3.50 (m, 2H),3.50-3.40 (m, 2H), 2.83-2.72 (m, 2H), 2.50 (q, 2H, J = 7.2 Hz),2.46-2.34 (m, 2H), 2.12-2.05 (m, 2H), 1.94-1.87 (m, 2H), 1.79-1.74 (m,1H), 1.14 (t, 3H, J = 7.2 Hz), 1.06-1.01 (m, 2H), 0.84-0.78 (m, 2H). 269

474 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.87 (d, 1H, J = 2.0 Hz), 7.83(d, 1H, J = 5.2 Hz), 7.56 (d, 2H, J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz),6.65 (d, 1H, J = 2.0 Hz), 5.83 (d, 1H, J = 5.2 Hz), 4.46 (heptet, 1H, J= 4.4 Hz), 3.97-3.90 (m, 2H), 3.90-3.85 (m, 2H), 3.60-3.50 (m, 2H),3.50-3.38 (m, 2H), 2.88-2.78 (m, 1H), 2.52 (q, 2H, J = 7.2 Hz),2.22-2.08 (m, 4H), 1.89-1.82 (m, 1H), 1.81-1.75 (m, 1H), 1.71-1.64 (m,1H), 1.55-1.43 (m, 1H), 1.12 (t, 3H, J = 7.2 Hz), 1.07-1.01 (m, 2H),0.85-0.78 (m, 2H). 270

474 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.29 (s, 1H), 8.10 (d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.73 (d, 2H, J = 8.8 Hz), 6.98 (d,1H, J = 1.6 Hz), 6.95 (d, 2H, J = 8.8 Hz), 5.97 (d, 1H, J = 5.6 Hz),3.92-3.89 (m, 4H), 3.71-3.70 (m, 2H), 3.54-3.50 (m, 2H), 3.48-3.43 (m,2H), 2.76-2.73 (m, 1H), 2.70-2.65 (m, 1H), 2.65- 2.62 (m, 2H), 2.60 (q,2H, J = 7.2 Hz), 2.51- 2.49 (m, 1H), 2.02-2.00 (m, 1H), 1.99-1.95 (m,1H), 1.59-1.56 (m, 1H), 1.06 (t, 3H, J = 7.2 Hz), 0.78-0.74 (m, 4H). 271

474 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 7.98 (d, 1H, J = 1.6 Hz), 7.84(d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.56 (d, 2H, J = 8.4 Hz),6.94 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.2 Hz), 4.04-3.98 (m, 2H),3.85-3.78 (m, 2H), 3.80-3.75 (m, 1H), 3.72-3.65 (m, 2H), 3.65- 3.58 (m,2H), 3.55-3.40 (m, 4H), 2.62-2.47 (m, 1H), 2.40-2.26 (m, 1H), 2.06-1.94(m, 1H), 1.45-1.35 (m, 6H), 0.95-0.83 (m, 4H). 272

474 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (s, 1H), 8.05 (d, 1H, J= 8.4 Hz), 6.95 (d, 2H, J = 8.4 Hz), 6.91 (d, 1H, J = 1.6 Hz), 5.94 (d,1H, J = 5.2 Hz), 3.94 (t, 4H, J = 7.6 Hz), 3.45- 3.38 (m, 10H),3.17-3.15 (m, 6H), 2.38 (q, 2H, J = 7.2 Hz), 2.17 (quintet, 2H, J = 7.6Hz), 1.04 (t, 3H, J = 7.2 Hz). 273

475 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.75- 7.73 (m, 2H), 6.99-6.96 (m, 3H), 5.97(d, 1H, J = 5.6 Hz), 4.11 (d, 1H, J = 5.6 Hz), 3.92 (br. s., 2H), 3.70(br. s., 3H), 3.52-3.45 (m, 4H), 2.95 (br. s., 4H), 2.784 (t, 2H, J =5.6 Hz), 2.61 (br. s., 4H), 2.06-1.99 (m, 1H), 0.78-0.75 (m, 4H). 274

485 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.06 (d, 1H, J = 1.6 Hz),7.87 (d, 1H, J = 4.8 Hz), 7.65 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.8Hz), 6.94 (s, 1H), 5.96 (d, 1H, J = 5.6 Hz), 4.44 (t, 1H, J = 5.2 Hz),3.93-3.91 (m, 2H), 3.71-3.69 (m, 2H), 3.56-3.45 (m, 6H), 3.15 (t, 4H, J= 4.4 Hz), 2.56 (t, 4H, J = 4.4 Hz), 2.44 (t, 2H, J = 6.4 Hz), 2.04-2.00(m, 1H), 0.78-0.72 (m, 4H). 275

475 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.12 (s, 1H), 7.88 (d, 1H, J= 5.6 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.24 (d, 2H, J = 8.0 Hz), 6.98 (s,1H), 6.59 (t, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 3.54-3.48 (m,4H), 3.45-3.40 (m, 4H), 3.09-3.05 (m, 2H), 2.89-2.85 (m, 2H), 2.73- 2.68(m, 1H), 2.45-2.40 (m, 1H), 2.23-2.17 (m, 2H), 1.78-1.72 (m, 2H),1.63-1.57 (m, 2H), 1.03 (t, 3H, J = 7.2 Hz), 0.93 (d, 6H, J = 7.2 Hz).276

475 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0Hz), 6.99 (d, 1H, J = 1.6 Hz), 6.60 (t, 1H, J = 5.6 Hz), 5.98 (d, 1H, J= 5.6 Hz), 3.53-3.51 (m, 4H), 3.44-3.43 (m, 4H), 3.10-3.05 (m, 2H),2.82-2.75 (m, 2H), 2.74-2.64 (m, 2H), 2.18- 2.15 (m, 2H), 1.83-1.81 (m,1H), 1.72-1.71 (m, 1H), 1.56-1.50 (m, 1H), 1.50-1.45 (m, 1H), 1.04 (t,3H, J = 7.2 Hz), 0.99-0.97 (m, 6H). 277

475 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J 1.2 Hz), 6.62 (t, 1H, J = 5.2 Hz), 5.99 (d, 1H, J =5.6 Hz), 3.52-3.51 (m, 4H), 3.44-3.43 (m, 4H), 3.10-3.05 (m, 2H),2.82-2.75 (m, 2H), 2.73-2.67 (m, 2H), 2.19- 2.16 (m, 2H), 1.83-1.81 (m,1H), 1.75-1.72 (m, 1H), 1.54-1.50 (m, 1H), 1.49-1.44 (m, 1H), 1.04 (t,3H, J = 7.2 Hz), 0.99-0.97 (m, 6H). 278

476 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.17 (s, 1H), 7.89 (d, 1H, J= 4.8 Hz), 7.75 (d, 2H, J = 7.6 Hz), 7.32 (d, 2H, J = 7.2 Hz), 7.04 (s,1H), 5.96 (d, 1H, J = 4.8 Hz), 4.78-4.62 (m, 1H), 3.92 (br. s., 2H),3.70 (br. s., 2H), 3.54 (br. s., 2H), 3.47 (br. s., 2H), 2.89-2.87 (m,1H), 2.66- 2.64 (m, 1H), 2.45-2.42 (m, 2H), 2.00-1.93 (m, 3H), 1.78-1.65(m, 2H), 1.22 (s, 1H), 1.03 (t, 3H, J = 6.4 Hz), 0.76-0.74 (m, 4H). 279

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.89 (d, 1H, J= 4.8 Hz), 7.75 (d, 2H, J = 7.6 Hz), 7.32 (d, 2H, J = 7.2 Hz), 7.04 (d,1H, J = 1.6 Hz), 5.96 (d, 1H, J = 4.8 Hz), 4.80-4.62 (m, 1H), 3.92 (br.s., 2H), 3.70 (br. s., 2H), 3.54 (br. s., 2H), 3.47 (br. s., 2H),2.89-2.87 (m, 1H), 2.70-2.60 (m, 1H), 2.45-2.42 (m, 2H), 2.03-1.94 (m,2H), 1.81-1.68 (m, 2H), 1.28 (s, 1H), 1.03 (t, 3H, J = 7.2 Hz),0.77-0.74 (m, 4H). 280

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.89 (d, 1H, J= 4.8 Hz), 7.75 (d, 2H, J = 7.6 Hz), 7.32 (d, 2H, J = 7.2 Hz), 7.04 (d,1H, J = 1.6 Hz), 5.96 (d, 1H, J = 4.8 Hz), 4.80-4.62 (m, 1H), 3.92 (s,2H), 3.70 (s, 2H), 3.54 (s, 2H), 3.47 (s, 2H), 2.89-2.87 (m, 1H),2.70-2.60 (m, 1H), 2.45-2.42 (m, 2H), 2.03-1.94 (m, 3H), 1.81-1.68 (m,2H), 1.28 (s, 1H), 1.03 (t, 3H, J = 7.2 Hz), 0.77-0.74 (m, 4H). 281

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (s, 1H), 7.90 (d, 1H, J= 5.2 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0 Hz), 7.04 (s,1H), 5.99 (d, 1H, J = 5.2 Hz), 5.05-4.88 (m, 1H), 3.92-3.89 (m, 2H),3.74-3.73 (m, 2H), 3.58- 3.48 (m, 6H), 3.00-2.97 (m, 2H), 2.35 (q, 2H, J= 6.8 Hz), 2.22-2.20 (m, 1H), 1.99-1.96 (m, 2H), 1.74-1.65 (m, 4H), 1.03(t, 3H, J = 6.8 Hz). 282

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J = 8.4Hz), 7.04 (s, 1H), 5.96 (d, 1H, J = 5.2 Hz), 5.26- 5.00 (m, 1H),4.00-3.86 (m, 2H), 3.76-3.64 (m, 2H), 3.54-3.50 (m, 2H), 3.45-3.40 (m,2H), 3.32-3.26 (m, 2H), 3.16-3.00 (m, 1H), 2.86- 2.70 (m, 1H), 2.46-2.36(m, 1H), 2.34-2.26 (m, 1H), 2.06-1.96 (m, 1H), 1.10-1.00 (m, 6H),0.80-0.70 (m, 4H). 283

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.25 (s, 1H), 7.90 (d, 1H, J= 5.6 Hz), 7.71-7.62 (m, 2H), 7.49-7.40 (m, 1H), 7.11 (m, 1H), 5.97 (d,1H, J = 5.6 Hz), 3.98-3.88 (m, 2H), 3.76-3.66 (m, 2H), 3.55-3.50 (m,2H), 3.50-3.45 (m, 2H), 3.43-3.33 (m, 2H), 3.32-3.28 (m, 1H), 3.00- 2.67(m, 3H), 2.30-2.23 (m, 1H), 2.06-1.98 (m, 1H), 1.96-1.90 (m, 1H),1.21-1.10 (m, 6H), 0.80-0.74 (m, 4H). 284

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.68- 7.64 (m, 1H), 7.61 (d, 1H, J = 8.0 Hz),7.41 (t, 1H, J = 8.0 Hz), 7.10 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6Hz), 3.95-3.91 (m, 2H), 3.73- 3.65 (m, 2H), 3.60-3.50 (m, 2H), 3.49-3.41(m, 2H), 3.32-3.27 (m, 1H), 3.10-2.92 (m, 1H), 2.82-2.74 (m, 2H),2.64-2.57 (m, 1H), 2.28- 2.19 (m, 1H), 2.04-1.98 (m, 1H), 1.86-1.78 (m,1H), 1.12-1.04 (m, 6H), 0.79-0.74 (m, 4H). 285

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.28- 8.27 (m, 2H), 8.14 (d,1H, J = 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.73 (d, 2H, J = 8.0 Hz),7.25 (d, 2H, J = 8.0 Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6Hz), 4.90-4.70 (m, 1H), 3.70-3.52 (m, 4H), 3.50-3.35 (m, 4H), 3.10- 2.90(m, 2H), 2.44 (q, 2H, J = 7.2 Hz), 2.15- 2.00 (m, 2H), 1.82-1.70 (m,4H), 1.70-1.60 (m, 1H), 1.30-1.12 (m, 6H), 1.04 (t, 3H, J = 7.2 Hz). 286

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.12 (s, 1H), 7.87 (d, 1H, J= 5.6 Hz), 7.69 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J = 8.0 Hz), 6.91 (s,1H), 5.94 (d, 1H, J = 5.6 Hz), 4.31-4.30 (m, 1H), 4.09-4.07 (m, 2H),3.89-3.85 (m, 2H), 3.85- 3.83 (m, 1H), 3.22-3.21 (m, 2H), 3.03-3.00 (m,1H), 3.00-2.97 (m, 2H), 3.50-2.45 (m, 1H), 2.35 (q, 2H, J = 7.2 Hz),1.99-1.94 (m, 2H), 1.73-1.68 (m, 2H), 1.68-1.63 (m, 2H), 1.29- 1.27 (d,3H, J = 6.4 Hz), 1.20 (t, 3H, J = 7.2 Hz), 1.02 (t, 3H, J = 7.2 Hz). 287

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4Hz), 6.97 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.08 (q, 2H, J= 7.2 Hz), 3.60-3.59 (m, 4H), 3.46-3.43 (m, 4H), 2.80-2.75 (m, 2H),2.72-2.67 (m, 2H), 2.18-2.08 (m, 2H), 1.82- 1.78 (m, 1H), 1.73-1.68 (m,1H), 1.58-1.51 (m, 1H), 1.47-1.40 (m, 1H), 1.21 (t, 3H, J = 7.2 Hz),1.11-1.10 (m, 6H). 288

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4Hz), 6.97 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.08 (q, 2H, J= 7.2 Hz), 3.60-3.59 (m, 4H), 3.46-3.43 (m, 4H), 2.80-2.75 (m, 2H),2.72-2.67 (m, 2H), 2.18-2.08 (m, 2H), 1.82- 1.78 (m, 1H), 1.73-1.68 (m,1H), 1.58-1.51 (m, 1H), 1.47-1.40 (m, 1H), 1.21 (t, 3H, J = 7.2 Hz),1.15-1.00 (m, 6H). 289

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 4.8 Hz), 7.65 (d, 2H, J = 8.8 Hz), 6.94 (d, 2H, J = 8.8Hz), 6.91 (d, 1H, J = 1.6 Hz), 6.60 (t, 1H, J = 5.6 Hz), 5.96 (d, 1H, J= 5.6 Hz), 3.52-3.51 (m, 4H), 3.43-3.41 (m, 4H), 3.15-3.14 (m, 4H),23.10-3.07 (m, 2H), 2.68-2.66 (m, 1H), 2.59- 2.58 (m, 4H), 1.03 (t, 3H,J = 7.2 Hz), 1.00 (d, 2H, J = 6.8 Hz). 290

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.44 (d, 1H, J = 2.0 Hz),8.23 (d, 1H, J = 1.2 Hz), 7.90 (d, 1H, J = 5.6 Hz), 7.84 (d, 1H, J = 8.4Hz), 7.67 (dd, 1H, J = 8.4, 2.0 Hz), 7.13 (d, 1H, J = 1.2 Hz), 6.60 (t,1H, J = 5.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.53-3.50 (m, 4H), 3.45-3.42(m, 4H), 3.33-3.31 (m, 1H), 3.11-3.04 (m, 2H), 2.90-2.87 (m, 2H),2.73-2.69 (m, 1H), 2.24- 2.19 (m, 2H), 1.78-1.75 (m, 2H), 1.70-1.63 (m,2H), 1.03 (t, 3H, J = 7.2 Hz), 0.98 (d, 6H, J = 6.8 Hz). 291

477 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 1.6 Hz),7.87 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.4Hz), 6.94 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.05-4.80 (m,1H), 4.00-3.80 (m, 2H), 3.78-3.65 (m, 2H), 3.60-3.50 (m, 1H), 3.49- 3.35(m, 3H), 3.30-3.21 (m, 4H), 3.20-3.05 (m, 4H), 2.36 (q, 2H, J = 7.2 Hz),2.30-2.10 (m, 1H), 1.60-1.40 (m, 1H), 1.10-1.00 (m, 1H), 1.03 (t, 3H, J= 7.2 Hz). 292

478 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 1.2 Hz),7.87 (d, 1H, J = 5.2 Hz), 7.65 (d, 2H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.4Hz), 6.95-6.933 (m, 1H), 5.96 (d, 1H, J = 5.2 Hz), 4.95-4.70 (m, 1H),4.00-3.85 (m, 2H), 3.70- 3.65 (m, 2H), 3.60-3.40 (m, 4H), 3.30-3.25 (m,4H), 3.18-3.10 (m, 4H), 2.70-2.60 (m, 1H), 2.36 (q, 2H, J = 7.2 Hz),1.50-1.30 (m, 1H), 1.25-1.10 (m, 1H), 1.03 (t, 3H, J = 7.2 Hz). 293

477 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 1.6 Hz),7.87 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.4 Hz), 6.95 (d, 2H, J = 8.4Hz), 6.94 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.04-4.80 (m,1H), 4.00-3.60 (m, 4H), 3.56-3.35 (m, 4H), 3.30-3.25 (m, 4H), 3.18- 3.10(m, 4H), 2.37 (q, 2H, J = 7.2 Hz), 2.23- 2.17 (m, 1H), 1.60-1.50 (m,1H), 1.10-1.00 (m, 1H), 1.03 (t, 3H, J = 7.2 Hz). 294

477 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 2.0 Hz),7.87 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.4 Hz), 6.96 (s, 1H), 6.94(d, 2H, J = 8.4 Hz), 5.97 (d, 1H, J = 5.6 Hz), 4.00-3.70 (m, 4H),3.60-3.45 (m, 4H), 3.30-3.25 (m, 4H), 3.18-3.10 (m, 4H), 2.37 (q, 2H, J= 7.2 Hz), 1.32-1.22 (m, 4H), 1.04 (t, 3H, J = 7.2 Hz). 295

477 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (s, 1H), 8.06 (d, 1H, J= 1.6 Hz), 7.86 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.4 Hz), 6.95 (d,2H, J = 8.4 Hz), 6.91 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz),4.08 (q, 2H, J = 7.2 Hz), 3.80- 3.70 (m, 8H), 3.25-3.05 (m, 4H),2.85-2.75 (m, 1H), 2.72-2.60 (m, 4H), 1.21 (t, 3H, J = 7.2 Hz), 1.05 (d,6H, J = 6.4 Hz). 296

481 1H-NMR (H-NMR (500 MHz, CDCl3) δ ppm 7.88 (s, 1H), 7.83 (d, 1H, J =5.5 Hz), 7.56 (d, 2H, J = 8.5 Hz), 6.97 (d, 2H, J = 8.5 Hz), 6.63 (s,1H), 5.83 (d, 1H, J = 5.0 Hz), 3.90-3.88 (m, 2H), 3.66-3.64 (m, 2H),3.48-3.44 (m, 4H), 3.23- 3.21 (m, 4H), 3.15-3.13 (m, 1H), 3.11-3.08 (m,4H), 3.02-2.92 (m, 2H), 2.82-2.73 (m, 2H). 297

481 1H-NMR (H-NMR (500 MHz, CDCl3) δ ppm 7.88 (d, 1H, J = 1.5 Hz), 7.894(d, 1H, J = 5.5 Hz), 7.57 (d, 2H, J = 9.0 Hz), 6.96 (d, 2H, J = 9.0 Hz),6.;66 (d, 1H, J = 1.5 Hz), 6.14 (td, 1H, J = 56.0, 4.5 Hz), 5.84 (d, 1H,J = 5.5 Hz), 4.00-3.84 (m, 5H), 3.60-3.44 (m, 4H), 3.43-3.34 (m, 2H),3.32-3.24 (m, 1H), 3.19-3.09 (m, 2H), 3.01- 2.93 (m, 1H), 1.83-1.75 (m,1H), 1.08-1.02 (m, 2H), 0.86-0.79 (m, 2H). 298

483 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.00-3.90 (m,2H), 3.75-3.65 (m, 2H), 3.60-3.55 (m, 2H), 2.54-2.50 (m, 2H), 3.30- 3.20(m, 1H), 3.05-2.97 (m, 1H), 2.95-2.90 (m, 1H), 2.80-2.60 (m, 2H),2.45-2.35 (m, 2H), 2.25-2.15 (m, 1H), 2.13-2.05 (m, 1H), 1.80- 1.70 (m,1H), 1.50-1.40 (m, 1H), 1.38-1.30 (m, 1H), 1.10-1.00 (m, 6H). 299

483 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.73 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.96-3.94 (m,2H), 3.71-3.70 (m, 2H), 3.58-3.55 (m, 2H), 3.49-3.47 (m, 2H), 3.29- 3.25(m, 1H), 3.02-2.96 (m, 1H), 2.95-2.90 (m, 1H), 2.73-2.69 (m, 2H),2.50-2.49 (m, 2H), 2.45-3.39 (m, 1H), 2.24-2.19 (m, 1H), 2.18- 2.08 (m,1H), 1.79-1.74 (m, 1H), 1.49-1.46 (m, 1H), 1.36-1.33 (m, 1H), 1.06 (t,3H, J = 6.4 Hz). 300

484 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.81 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.22 (t, 2H, J= 8.8 Hz), 4.11-4.08 (m, 2H), 3.80-3.73 (m, 4H), 3.55-3.30 (s, 9H),3.25-3.20 (m, 2H), 3.10-3.04 (m, 1H), 2.40- 2.42 (m, 1H), 2.10-2.00(br., 1H), 1.27 (t, 3H, J = 7.2 Hz). 301

484 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.08 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.67 (d, 2H, J = 8.4 Hz), 6.99-6.95 (m, 3H),5.99 (d, 1H, J = 5.6 Hz), 3.96-3.88 (m, 2H), 3.75-3.66 (m, 1H),3.65-3.52 (m, 2H), 3.50-3.45 (m, 1H), 3.41-3.36 (m, 1H), 3.23-3.07 (m,4H), 2.68- 2.62 (m, 2H), 2.58-2.54 (m, 1H), 2.22-2.15 (m, 1H), 1.54-1.50(m, 1H), 1.39-1.34 (m, 1H), 1.26-1.22 (m, 1H), 1.12-1.01 (m, 3H). 302

484 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.09 (s, 1H), 7.88 (d, 1H, J= 5.2 Hz), 7.68 (d, 2H, J = 8.4 Hz), 6.98 (d, 2H, J = 8.4 Hz), 6.97 (s,1H), 5.98 (d, 1H, J = 5.2 Hz), 4.00-3.91 (m, 2H), 3.75-3.66 (m, 2H),3.61-3.51 (m, 3H), 3.50- 3.43 (m, 2H), 3.21-3.08 (m, 4H), 2.96-2.91 (m,1H), 2.13-2.08 (m, 1H), 1.50-1.44 (m, 1H), 1.38-1.32 (m, 1H), 1.27-1.21(m, 1H), 1.17- 1.02 (m, 3H). 303

484 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.2 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.70 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.4Hz), 6.97 (d, 1H, J = 1.2 Hz), 5.94 (d, 1H, J = 5.6 Hz), 4.21 (t, 2H, J= 8.4 Hz), 4.08 (dd, 2H, J = 7.2, 6.0 Hz), 3.78-3.71 (m, 1H), 3.46-3.45(m, 8H), 3.37-3.24 (m, 2H), 2.91 (t, 1H, J = 8.4 Hz), 2.71-2.59 (m, 2H),2.49-2.40 (m, 2H), 2.27-2.18 (m, 1H), 1.79-1.71 (m, 1H), 1.05 (t, 3H, J= 7.2 Hz). 304

484 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.2 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.4Hz), 6.98 (d, 1H, J = 1.2 Hz), 5.94 (d, 1H, J = 5.6 Hz), 4.21 (t, 2H, J= 8.4 Hz), 4.08 (dd, 2H, J = 7.2, 6.0 Hz), 3.78-3.71 (m, 1H), 3.46-3.45(m, 8H), 3.32-3.26 (m, 2H), 2.96 (t, 1H, J = 8.4 Hz), 2.75-2.64 (m, 2H),2.50-2.44 (m, 2H), 2.28-2.19 (m, 1H), 1.81-1.72 (m, 1H), 1.06 (t, 3H, J= 7.2 Hz). 305

484 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.2 Hz), 5.96 (d, 1H, J = 5.2 Hz), 3.92-3.91 (m,2H), 3.70-3.69 (m, 2H), 3.53-3.50 (m, 2H), 3.49-3.45 (m, 2H), 3.35- 3.30(m, 1H), 2.80-2.78 (m, 2H), 2.69-2.66 (m, 2H), 2.06-1.95 (m, 3H),1.79-1.68 (m, 6H), 1.62-1.58 (m, 2H), 1.58-1.55 (m, 1H), 0.77- 0.74 (m,4H). 306

485 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 1.7 Hz, 1H),7.74-7.62 (m, 3H), 7.32-7.18 (m, 3H), 5.60 (d, J = 5.9 Hz, 1H), 4.83 (s,1H), 4.40 (s, 1H), 4.22 (d, J = 11.6 Hz, 2H), 3.98 (d, J = 11.5 Hz, 1H),3.85 (d, J = 11.3 Hz, 1H), 2.87 (d, J = 10.9 Hz, 2H), 2.69 (q, J = 7.2Hz, 2H), 2.48-2.38 (m, 1H), 2.20 (t, J = 11.3 Hz, 2H), 1.74 (q, J = 7.1,4.5 Hz, 3H), 1.69-1.48 (m, 3H), 0.98 (d, J = 6.6 Hz, 6H), 0.91-0.72 (m,2H), 0.71 (s, 1H), 0.51 (s, 1H). 307

485 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.30 (br. s., 1H), 8.06 (s,1H), 7.87 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.0 Hz), 6.95 (d, 2H, J= 8.0 Hz), 6.93 (s, 1H), 5.96 (d, 1H, J = 5.2 Hz), 3.95-3.90 (br., 2H),3.71-3.45 (m, 8H), 2.79- 2.66 (m, 2H), 2.38-2.33 (m, 1H), 2.27-2.20 (m,1H), 2.03-1.92 (m, 2H), 1.74-1.45 (m, 4H), 1.31-1.08 (m, 4H), 0.77-0.74(m, 4H). 308

485 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 8.03 (d, 1H, J= 1.6 Hz), 7.86 (d, 1H, J = 5.6 Hz), 7.62 (d, 2H, J = 8.8 Hz), 6.00 (d,1H, J = 1.6 Hz), 6.45 (d, 2H, J = 8.8 Hz), 5.96 (d, 1H, J = 5.6 Hz),3.96-3.89 (m, 6H), 3.72-3.68 (m, 2H), 3.45-3.45 (m, 9H), 2.04-2.00 (m,1H), 0.91 (d, 6H, J = 6.0 Hz), 0.78-0.74 (m, 4H). 309

486 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.11 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.2 Hz), 7.73 (d, 2H, J = 8.4 Hz), 6.99 (d, 2H, J = 8.4Hz), 6.94 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.48-4.41 (m,1H), 4.22 (d, 2H, J = 8.4 Hz), 4.09 (dd, 2H, J = 8.4, 6.4 Hz), 3.80-3.72(m, 1H), 3.47-3.45 (m, 8H), 3.21-3.18 (m, 1H), 2.92-2.86 (m, 1H),2.82-2.67 (m, 2H), 2.01- 1.96 (m, 1H), 1.80-1.72 (m, 1H), 1.68-1.60 (m,1H), 1.57-1.43 (m, 2H). 310

486 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.16 (s, 1H), 7.90 (d, 2H, J= 5.2 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0 Hz), 7.03 (s,1H), 5.97 (d, 1H, J = 5.6 Hz), 4.55 (t, 2H, J = 6.4 Hz), 4.45 (t, 2H, J= 6.4 Hz), 3.93 (br. s., 2H), 3.71 (br. s., 2H), 3.54-3.47 (m, 4H),3.42-3.35 (m, 2H), 2.82-2.79 (m, 2H), 2.06-2.00 (m, 1H), 1.86-1.64 (m,6H), 0.78-0.75 (m, 4H). 311

486 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 3.73-3.71 (m,2H), 3.64-3.62 (m, 2H), 3.48-3.46 (m, 4H), 3.30-3.25 (m, 1H), 2.96- 2.92(m, 1H), 2.73-2.65 (m, 2H), 2.46-2.42 (m, 1H), 2.25-2.19 (m, 1H), 2.09(s, 3H), 2.03-1.92 (m, 1H), 1.80-1.72 (m, 1H), 1.49-1.46 (m, 2H),1.34-1.31 (m, 2H), 1.06 (t, 3H, J = 7.2 Hz). 312

486 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.2 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.65-3.66 (m,2H), 3.55-3.52 (m, 2H), 3.46-3.43 (m, 4H), 3.42-3.39 (m, 1H), 2.85- 2.75(m, 2H), 2.73-2.65 (m, 2H), 2.22-2.17 (m, 2H), 2.16-2.09 (m, 4H),1.95-1.87 (m, 1H), 1.85-1.78 (m, 1H), 1.77-1.69 (m, 2H), 1.60- 1.50 (m,1H), 1.50-1.39 (m, 1H), 0.95-0.98 (m, 6H). 313

486 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.0Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.92-3.91 (m,2H), 3.70-3.68 (m, 2H), 3.55-3.50 (m, 2H), 3.50-3.45 (m, 2H), 2.82- 2.78(m, 2H), 2.50-2.45 (m, 2H), 2.40-2.35 (m, 1H), 2.22-2.17 (m, 1H),2.03-1.98 (m, 1H), 1.78-1.72 (m, 2H), 1.67-1.60 (m, 2H), 1.57- 1.49 (m,1H), 1.30-1.22 (m, 1H), 0.92 (d, 3H, J = 6.8 Hz), 0.86 (t, 3H, J = 7.6Hz), 0.78-0.71 (m, 4H). 314

487 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.88 (d, 1H, J = 1.6 Hz), 7.83(d, 1H, J = 5.2 Hz), 7.57 (d, 2H, J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz),6.66 (d, 1H, J = 0.8 Hz), 5.83 (d, 1H, J = 5.2 Hz), 4.73-4.66 (m, 4H),3.95-3.88 (m, 4H), 3.59-3.46 (m, 5H), 3.29-3.27 (m, 4H), 2.54- 2.52 (m,4H), 1.81-1.76 (m, 1H), 1.07-1.03 (m, 2H), 0.85-0.81 (m, 2H). 315

487 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (s, 1H), 8.07 (d, 1H, J= 1.6 Hz), 7.87 (d, 1H, J = 4.8 Hz), 7.65 (d, 2H, J = 8.8 Hz), 6.96 (d,2H, J = 8.8 Hz), 6.94 (s, 1H), 5.96 (d, 1H, J = 5.6 Hz), 3.95-3.90 (br.,2H), 3.79-3.65 (m, 5H), 3.57-3.46 (m, 6H), 3.20-3.15 (m, 1H), 2.84- 2.67(m, 3H), 2.33-2.20 (m, 4H), 2.04-2.00 (m, 1H), 0.79-0.74 (m, 4H). 316

487 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.63 (d, 2H, J = 8.8 Hz), 6.94-6.91 (m, 3H),5.95 (d, 1H, J = 5.6 Hz), 3.95-3.85 (m, 2H), 3.75-3.65 (m, 2H),3.60-3.40 (m, 4H), 3.14-3.10 (m, 2H), 2.88 (s, 2H), 2.63-2.59 (m, 2H),2.39 (q, 2H, J = 7.2 Hz), 2.05-1.95 (m, 1H), 1.05 (s, 6H), 0.99 (t, 3H,J = 7.2 Hz), 0.80-0.70 (m, 4H). 317

487 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.96 (d, m1H, J = 5.6 Hz), 3.46-3.45 (m,4H), 3.41-3.40 (m, 4H), 3.34-3.31 (m, 4H), 3.01-2.98 (m, 2H), 2.36 (q,2H, J = 7.2 Hz), 2.01-1.95 (m, 2H), 1.80-1.72 (m, 8H), 1.70-1.64 (m,1H), 1.02 (t, 3H, J = 7.2 Hz). 318

487 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.08 (d, 1H, J = 1.0 Hz),7.86 (d, 1H, J = 5.5 Hz), 7.63 (d, 2H, J = 8.5 Hz), 6.96 (d, 1H, J = 8.5Hz), 6.87 (d, 1H, J = 2.0 Hz), 5.95 (d, 1H, J = 5.5 Hz), 4.66-4.65 (m,1H), 4.21-4.16 (m, 1H), 3.95-3.93 (m, 1H), 3.93-3.90 (m, 1H), 3.22- 3.19(m, 2H), 3.19-3.09 (m, 4H), 2.70-2.65 (m, 1H), 2.60-2.54 (m, 4H),2.01-1.96 (m, 1H), 1.43-1.35 (m, 2H), 1.30-1.21 (m, 2H), 1.06- 0.96 (m,6H), 0.82-0.71 (m, 4H). 319

488 1H-NMR (H-NMR (400 MHz, Methanol-d4) δ 7.90 (d, J = 1.8 Hz, 1H),7.72 (d, J = 5.4 Hz, 1H), 7.67- 7.59 (m, 2H), 7.30-7.20 (m, 2H), 6.82(d, J = 1.8 Hz, 1H), 5.72 (d, J = 5.5 Hz, 1H), 4.73 (d, J = 33.7 Hz,2H), 3.97 (d, J = 11.7 Hz, 2H), 3.44 (d, J = 11.8 Hz, 2H), 3.15-3.00 (m,4H), 2.95 (q, J = 7.0 Hz, 1H), 2.79 (p, J = 6.5 Hz, 1H), 2.54 (tt, J =12.1, 4.3 Hz, 1H), 2.36 (td, J = 11.8, 2.8 Hz, 3H), 1.90-1.67 (m, 5H),1.12 (dd, J = 6.7, 3.8 Hz, 7H), 1.02 (t, J = 7.2 Hz, 2H).H-NMR ( 320

488 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 6.0 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.4Hz), 7.00 (d, 1H, J = 1.2 Hz), 5.96 (d, 1H, J = 5.2 Hz), 5.10 (d, 1H, J= 6.0 Hz), 4.20-4.00 (m, 1H), 3.70-3.60 (m, 2H), 3.58-3.50 (m, 2H),3.48-3.35 (m, 4H), 3.30-3.15 (m, 2H), 3.05- 2.95 (m, 1H), 2.80-2.60 (m,2H), 2.47-2.30 (m, 4H), 2.25-2.15 (m, 1H), 2.10-2.00 (m, 2H), 1.80-1.70(m, 1H), 1.10-1.00 (m, 6H). 321

488 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.92 (d, 1H, J = 1.6 Hz), 7.85(d, 1H, J = 5.2 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0 Hz),6.68 (d, 1H, J = 1.6 Hz), 5.84 (d, 1H, J = 5.2 Hz), 4.54-4.48 (m, 1H),3.92-3.83 (m, 2H), 3.65-3.57 (m, 2H), 3.50-3.42 (m, 4H), 3.41- 3.37 (m,1H), 3.35-3.25 (m, 2H), 3.11-3.00 (m, 1H), 2.81-2.72 (m, 1H), 2.69-2.63(m, 2H), 2.59-2.51 (m, 2H), 2.40-2.32 (m, 1H), 2.28- 2.21 (m, 2H),1.99-1.94 (m, 2H), 1.20-1.16 (dd, 6H, J = 6.4, 1.2 Hz). 322

488 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.36 (s, 1H), 8.14 (d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.25 (d,2H, J = 8.0 Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz),4.86 (quintet, 1H, J = 7.2 Hz), 3.60-3.52 (m, 4H), 3.50-3.40 (m, 4H),3.10- 2.90 (m, 2H), 2.48-2.42 (m, 1H), 2.36 (q, 2H, J = 7.2 Hz),2.30-2.20 (m, 2H), 2.10-1.90 (m, 4H), 1.80-1.62 (m, 4H), 1.60-1.50 (m,2H), 1.02 (t, 3H, J = 7.2 Hz). 323

488 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26- 8.17 (m, 1H), 7.92-7.88(m, 1H), 7.77-7.72 (m, 2H), 7.57 (d, 2H, J = 7.6 Hz), 7.05 (s, 1H), 5.98(d, 1H, J = 5.6 Hz), 4.56-4.44 (m, 1H), 4.00-3.80 (m, 2H), 3.80-3.60 (m,2H), 3.60- 3.50 (m, 2H), 3.50-3.40 (m, 2H), 3.31-3.00 (m, 1H), 2.902.75(m, 1H), 2.70-2.51 (m, 1H), 2.45-2.38 (m, 1H), 2.05-1.98 (m, 2H), 1.90-1.79 (m, 2H), 1.58-1.50 (m, 1H), 1.50-1.41 (m. 1H), 1.03-0.98 (m, 6H),0.79-0.73 (m, 4H). 324

488 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 7.89 (s, 1H), 7.75 (d, 1H, J =5.6 Hz), 7.66 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.8 Hz), 6.84 (s,1H), 5.90 (d, 1H, J = 5.6 Hz), 3.93 (m, 2H), 3.75 (m, 2H), 3.53-3.33 (m,9H), 2.28-2.19 (m, 2H), 1.99-1.94 (m, 2H), 1.91 (m, 1H), 1.33 (d, 6H, J= 6.4 Hz), 0.85-0.83 (m, 2H), 0.78-0.74 (m, 2H). 325

488 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.90 (d, 1H, J= 5.6 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.56 (d, 2H, J = 8.0 Hz), 7.05 (s,1H), 5.98 (d, 1H, J = 5.6 Hz), 4.53-4.48 (m, 1H), 4.00-3.80 (m, 2H),3.80-3.65 (m, 2H), 3.60- 3.50 (m, 2H), 3.50-3.40 (m, 2H), 3.33-3.25 (m,1H), 2.85-2.51 (m, 2H), 2.50-2.30 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.70(m, 2H), 1.62- 1.55 (m, 1H), 1.55-1.48 (m, 1H), 1.15-0.85 (m, 6H),0.79-0.70 (m, 4H). 326

488 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (s, 1H), 7.91 (d, 1H, J= 5.6 Hz), 7.89-7.65 (m, 2H), 7.57 (d, 2H, J = 8.0 Hz), 7.06 (s, 1H),5.98 (d, 1H, J = 5.6 Hz), 4.00-3.85 (m, 2H), 3.80-3.65 (m, 2H),3.60-3.50 (m, 2H), 3.50- 3.40 (m, 2H), 3.33-3.25 (m, 1H), 2.50-2.10 (m,4H), 2.05-1.40 (m, 5H), 1.30-0.80 (m, 6H), 0.79-0.70 (m, 4H). 327

488 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.05 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.65- 7.63 (m, 2H), 6.96-6.94 (m, 2H), 6.91(d, 1H, J = 1.2 Hz), 5.95 (d, 1H, J = 5.6 Hz), 3.44-3.40 (m, 4H),3.39-3.35 (m, 8H), 3.16 (br. s., 4H), 2.56 (br. s., 4H), 2.49 (br. s.,2H), 1.76 (br. s., 4H), 1.05 (d, 3H, J = 7.2 Hz). 328

488 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (s, 1H), 8.02 (d, 1H, J= 1.6 Hz), 7.85 (d, 1H, J = 5.6 Hz), 7.61 (d, 2H, J = 8.4 Hz), 6.88 (s,1H), 6.61 (t, 1H, J = 5.6 Hz), 6.44 (d, 2H, J = 8.4 Hz), 5.96 (d, 1H, J= 5.6 Hz), 3.87 (s, 4H), 3.55-3.50 (m, 4H), 3.48-3.45 (m, 4H), 3.32 (s,4H), 3.15-3.04 (m, 2H), 2.34-2.32 (m, 1H), 1.03 (t, 3H, J = 7.2 Hz),0.87 (d, 6H, J = 6.4 Hz). 329

489 330

489 331

489 332

489 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.85 (d, 1H, J = 1.76 Hz), 7.82(d, 1H, J = 5.2 Hz), 7.51 (d, 2H, J = 8.4 Hz), 6.62 (d, 1H, J = 1.6 Hz),6.51 (d, 1H, J = 8.4 Hz), 5.83 (d, 1H, J = 5.2 Hz), 4.93-4.70 (m, 1H),4.13-4.05 (m, 1H), 4.03-3.95 (m, 1H), 3.93-3.84 (m, 1H), 3.80- 3.71 (m,1H), 3.68-3.60 (m, 1H), 3.58-3.50 (m, 1H), 3.47-3.41 (m, 1H), 3.38 (s,1H), 3.38-3.32 (m, 1H), 2.46 (q, 2H, J = 7.2 Hz), 1.97-1.95 (m, 1H),1.95-1.90 (m, 1H), 1.14-1.06 (m, 1H), 0.98 (t, 3H, J = 7.2 Hz). 333

489 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 8.56 (s, 1H), 7.86 (d, 1H, J =1.6 Hz), 7.83 (d, 1H, J = 5.2 Hz), 7.52 (d, 2H, J = 8.4 Hz), 6.63 (d,1H, J = 1.6 Hz), 6.51 (d, 2H, J = 8.4 Hz), 5.84 (d, 1H, J = 5.2 Hz),4.93-4.70 (m, 1H), 4.13-4.05 (m, 1H), 4.04-4.01 (m, 4H), 4.00-3.95 (m,1H), 3.94-3.83 (m, 1H), 3.80-3.75 (m, 1H), 3.72- 3.70 (m, 4H), 3.68-3.60(m, 1H), 3.59-3.50 (m, 1H), 3.48-3.45 (m, 1H), 3.42-3.39 (m, 1H), 2.782(q, 2H, J = 7.2 Hz), 1.98-1.92 (m, 1H), 1.92-1.87 (m, 1H), 1.15-1.05 (m,4H). 334

489 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.88 (d, 1H, J = 2.0 Hz), 7.82(d, 1H, J = 5.2 Hz), 7.55 (d, 2H, J = 8.8 Hz), 6.97 (d, 2H, J = 8.8 Hz),6.66 (d, 1H, J = 2.0 Hz), 5.83 (d, 1H, J = 6.0 Hz), 3.94-3.86 (m, 4H),3.57 (t, 2H, J = 5.6 Hz), 3.58-3.46 (m, 4H), 3.38 (s, 3H), 3.27 (t, 4H,J = 5.2 Hz), 2.70 (t, 4H, J = 5.2 Hz), 2.67 (t, 2H, J = 5.6 Hz),1.80-1.76 (m, 1H), 1.06- 1.03 (m, 2H), 0.84-0.81 (m, 2H). 335

489 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.87 (d, 1H, J = 1.6 Hz), 7.82(d, 1H, J = 5.2 Hz), 7.56 (d, 2H, J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz),6.63 (d, 1H, J = 1.6 Hz), 5.82 (d, 1H, J = 5.2 Hz), 4.24-4.21 (m, 1H),3.88-3.84 (m, 2H), 3.66-3.62 (m, 2H), 3.45-3.40 (m, 4H), 3.37- 3.30 (m,4H), 2.82-2.78 (m, 1H), 2.78-2.73 (m, 4H), 2.65-2.57 (m, 4H), 2.26-2.23(m, 2H), 1.26-1.20 (m, 3H). 336

489 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.87 (d, 1H, J = 2.0 Hz), 7.82(d, 1H, J = 5.6 Hz), 7.56 (d, 2H, J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz),6.63 (d, 1H, J = 2.0 Hz), 5.82 (d, 1H, J = 5.6 Hz), 4.51 (quintet, 1H, J= 6.4 Hz), 3.88-3.85 (m, 2H), 3.62-3.58 (m, 2H), 3.45-3.42 (m, 4H),3.30-3.25 (m, 5H), 2.69-2.62 (m, 6H), 2.50 (d, 2H, J = 7.2 Hz),2.27-2.19 (m, 2H), 1.16 (t, 3H, J = 7.2 Hz). 337

489 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.2 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J = 8.0Hz), 7.0 (d, 1H, J = 1.2 Hz), 5.96 (d, 1H, J = 5.6 Hz), 5.09 (d, 1H, J =5.6 Hz), 4.14-4.09 (m, 1H), 3.69-3.66 (m, 2H), 3.55-3.52 (m, 2H),3.46-3.41 (m, 4H),3.26-3.18 (m, 1H), 2.99- 2.96 (m, 2H), 2.43-2.37 (m,3H), 2.34 (q, 2H, J = 7.2 Hz), 2.10-2.02 (m, 2H), 1.97-1.92 (m, 2H),1.77-1.70 (m, 2H), 1.68-1.61 (m, 2H), 1.02 (t, 3H, J = 7.2 Hz). 338

489 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (br s, 1H), 8.03 (d, 1H,J = 1.6 Hz), 7.87 (d, 1H, J = 5.6 Hz), 7.61 (d, 2H, J = 8.4 Hz), 6.88(d, 1H, J = 1.6 Hz), 6.44 (d, 2H, J = 8.4 Hz), 5.96 (d, 2H, J = 5.6 Hz),4.09 (q, 2H, J = 7.2 Hz), 3.87 (s, 4H), 3.63-3.57 (m, 4H), 3.47-3.41 (m,4H), 3.28 (s, 4H), 2.30-2.22 (m, 1H), 1.22 (t, 3H, J = 7.2 Hz), 0.86 (d,6H, J = 6.4 Hz). 339

489 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (s, 1H), 7.88 (d, 1H, J= 5.6 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0 Hz), 6.91 (s,1H), 6.52 (t, 1H, J = 5.2 Hz), 5.97 (d, 1H, J = 5.6 Hz), 4.32-4.28 (m,1H), 3.88-3.80 (m, 3H), 3.32-3.31 (m, 1H), 3.29-3.24 (m, 1H), 3.18- 3.14(m, 1H), 3.12-3.06 (m, 2H), 3.02-2.96 (m, 1H), 2.92-2.86 (m, 2H),2.74-2.68 (m, 1H), 2.46-2.42 (m, 1H), 2.25-2.20 (m, 2H), 1.78- 1.72 (m,2H), 1.66-1.56 (m, 2H), 1.24 (d, 3H, J = 6.0 Hz), 1.04 (t, 3H, J = 7.2Hz), 1.00 (d, 6H, J = 6.4 Hz). 340

489 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (s, 1H), 8.14 (d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.25 (d,2H, J = 8.4 Hz), 7.00 (d, 1H, J = 1.6 Hz), 6.32 (d, 1H, J = 7.6 Hz),5.98 (d, 1H, J = 5.6 Hz), 3.82- 3.75 (m, 12H), 3.54-3.50 (m, 4H),3.46-3.41 (m, 4H), 3.03-2.98 (m, 2H), 2.92-2.86 (m, 1H), 2.52-2.50 (m,1H), 2.44-2.36 (m, 2H), 1.85- 1.75 (m, 2H), 1.72-1.68 (m, 2H), 1.10-1.05(m. 12H). 341

489 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (s, 1H), 8.14 (d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.25 (d,2H, J = 8.4 Hz), 7.00 (d, 1H, J = 1.6 Hz), 6.62 (t, 1H, J = 5.2 Hz),5.98 (d, 1H, J = 5.6 Hz), 3.54- 3.50 (m, 4H), 3.46-3.41 (m, 4H),3.03-2.94 (m, 4H), 2.88-2.83 (m, 1H), 2.52-2.50 (m, 1H), 2.40-2.32 (m,2H), 1.84-1.77 (m, 2H), 1.75- 1.66 (m, 2H), 1.43 (q, 2H, J = 7.2 Hz),1.05 (d, 6H, J = 6.8 Hz), 0.85 (t, 3H, J = 7.2 Hz). 342

489 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.25 (s, 1H), 8.15 (d, 1H, J= 1.6 Hz), 7.90 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.25 (d,2H, J = 8.4 Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz),3.50-3.45 (m, 4H), 3.36-3.30 (m, 4H), 3.17 (q, 2H, J = 7.2 Hz),3.05-3.02 (m, 2H), 2.95-2.92 (m, 1H), 2.79 (s, 3H), 2.59- 2.56 (m, 1H),2.50-2.44 (m, 2H), 1.86-1.80 (m, 2H), 1.78-1.70 (m, 2H), 1.12-1.05 (m,9H). 343

490 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0Hz), 7.03 (d, 1H, J = 1.2 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.65-4.50 (m,1H), 4.40-4.30 (m, 1H), 3.95-3.85 (m, 1H), 3.79-3.75 (m, 2H), 3.70- 3.65(m, 2H), 3.60-3.55 (m, 2H), 3.52-3.45 (m, 2H), 3.42-3.38 (m, 2H),3.00-2.85 (m, 1H), 2.80-2.65 (m, 2H), 2.60-2.52 (m, 2H), 1.90- 1.80 (m,2H), 1.70-1.60 (m, 2H), 1.50-1.30 (m, 2H), 1.25-1.10 (m, 2H). 344

490 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.05 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.8Hz), 6.91 (d, 1H, J = 1.6 Hz), 5.94 (d, 1H, J = 5.2 Hz), 5.61 (d, 1H, J= 6.0 Hz), 4.43-4.69 (m, 1H), 4.10 (t, 2H, J = 8.8 Hz), 3.70 (dd, 2H, J= 8.8, 4.8 Hz), 2.45-2.41 (m, 8H), 3.35-32.30 (m, 4H), 3.17-3.15 (m,4H), 2.37 (q, 2H, J = 7.2 Hz), 1.04 (t, 3H, J = 7.2 Hz). 345

490 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.22 (s, 1H), 7.90 (d, 1H, J= 5.6 Hz), 7.65 (s, 1H), 7.62-7.59 (m, 1H), 7.34-7.30 (m, 1H), 7.09 (s,1H), 5.97 (d, 1H, J = 5.6 Hz), 3.92-3.91 (m, 2H), 3.71-3.69 (m, 2H),3.54-3.50 (m, 2H), 3.50-3.46 (m, 2H), 2.90-2.87 (m, 2H), 2.73- 2.70 (m,2H), 2.25-2.21 (m, 2H), 2.20-2.19 (m, 1H), 2.00-1.70 (m, 4H), 0.99 (d,6H, J = 6.4 Hz), 0.77-0.73 (m, 4H). 346

490 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.8 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H),6.99 (d, J = 1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.81 (p, J = 6.2 Hz,1H), 3.58 (q, J = 5.6, 5.1 Hz, 4H), 3.44 (t, J = 5.2 Hz, 4H), 2.91 (s,2H), 2.23 (s, 1H), 1.73 (d, J = 52.3 Hz, 5H), 1.21 (d, J = 6.2 Hz, 6H),1.03 (bs, 8H). 347

491 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 1.7 Hz, 1H), 7.87(d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H),6.97 (d, J = 1.9 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 5.90 (s, 1H), 3.45(ddd, J = 28.3, 7.6, 4.0 Hz, 9H), 2.88 (d, J = 10.8 Hz, 2H), 2.80-2.57(m, 1H), 2.21 (t, J = 11.1 Hz, 2H), 1.76 (d, J = 12.4 Hz, 2H), 1.70-1.49(m, 2H), 1.27 (s, 9H), 0.99 (d, J = 6.5 Hz, 6H). 348

490 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.04 (d, 1H, J = 1.6 Hz),7.85 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.4 Hz), 6.93 (d, 2H, J = 8.4Hz), 6.90 (d, 1H, J = 1.6 Hz), 6.31 (d, 1H, J = 7.6 Hz), 5.96 (d, 1H, J= 5.6 Hz), 3.80-3.70 (m, 1H), 3.54-3.48 (m, 4H), 3.44-3.36 (m, 4H),3.20-3.10 (m, 4H), 2.72-2.62 (m, 1H), 2.60- 2.54 (m, 4H), 1.07 (d, 6H, J= 6.4 Hz), 1.00 (d, 6H, J = 6.4 Hz). 349

491 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.89 (d, 1H, J = 1.6 Hz), 7.84(d, 1H, J = 5.2 Hz), 7.57 (d, 2H, J = 8.4 Hz), 6.98 (d, 2H, J = 8.4 Hz),6.66 (d, 1H, J = 1.6 Hz), 5.85 (d, 1H, J = 8.4 Hz), 4.95-4.75 (m, 1H),3.96-3.92 (m, 2H), 3.90-3.84 (m, 2H), 3.90-3.84 (m, 2H), 3.58- 3.54 (m,2H), 2.49-3.43 (m, 2H), 3.41-3.35 (m. 4H), 2.98-2.90 (m, 1H), 2.90-2.83(m, 4H), 2.33-2.20 (m, 1H), 1.47-1.40 (m, 2H), 1.22 (d, 6H, J = 5.6 Hz).350

491 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 1.6 Hz),7.87 (d, 1H, J = 5.2 Hz), 7.65 (d, 2H, J = 8.8 Hz), 6.95 (d, 1H, J = 1.6Hz), 6.94 (d, 2H, J = 8.8 Hz), 5.97 (d, 1H, J = 5.2 Hz), 5.06-4.85 (m,1H), 3.97-3.85 (m, 2H), 3.74-7.71 (m, 2H), 3.60-3.43 (m, 4H), 3.15- 3.12(m, 4H), 2.66 (heptet, 1H, J = 6.4 Hz), 2.51-2.49 (m, 4H), 2.24-2.19 (m,1H), 1.60- 1.50 (m, 1H), 1.08-1.03 (m, 1H), 1.01 (d, 6H, J = 6.4 Hz).351

491 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.90 (d, 1H, J= 6.0 Hz), 7.77 (d, 2H, J = 8.0 Hz), 7.56 (d, 2H, J = 8.0 Hz), 7.02 (s,1H), 6.61 (t, 1H, J = 5.6 Hz), 5.99 (d, 1H, J = 5.2 Hz), 3.55-3.50 (m,4H), 3.48-3.43 (m, 4H), 3.43-3.33 (m, 2H), 3.33-3.25 (m, 2H), 3.20- 3.05(m, 2H), 1.91-1.74 (m, 2H), 1.70-1.45 (m, 2H), 1.14-0.95 (m, 9H). 352

491 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (s, 1H), 7.88 (d, 1H, J= 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.48 (d, 2H, J = 8.4 Hz), 7.01 (d,1H, J = 1.6 Hz), 6.61 (t, 1H, J = 5.2 Hz), 5.98 (d, 1H, J = 5.6 Hz),4.74 (s, 1H), 3.52-3.51 (m, 4H), 3.44-3.43 (m, 4H), 3.13-3.05 (m, 2H),2.74-2.70 (m, 1H), 2.60-2.57 (m, 4H), 1.95- 1.85 (m, 2H), 1.63-1.60 (m,2H), 1.04 (t, 3H, J = 7.2 Hz), 1.00 (d, 6H, J = 6.4 Hz). 353

491 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 6.63 (t, 1H, J = 5.6 Hz), 5.97 (d, 1H, J= 5.6 Hz), 4.65 (t, 1H, J = 5.6 Hz), 3.55-3.52 (m, 4H), 3.48-3.40 (m,6H), 3.12 (q, 2H, J = 5.6 Hz), 2.90-2.86 (m, 2H), 2.74-2.68 (m, 1H),2.50-2.45 (m, 1H), 2.25- 2.18 (m, 2H), 1.80-1.74 (m, 2H), 1.65-1.60 (m,2H), 1.00 (d, 6H, J = 6.4 Hz). 354

493 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.22 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.65 (s, 1H), 7.65-7.60 (m, 1H), 7.33-7.30 (m,1H), 7.06 (d, 1H, J = 1.6 Hz), 6.61 (t, 1H, J = 5.2 Hz), 5.97 (d, 1H, J= 5.6 Hz), 3.51-3.50 (m, 4H), 3.43-3.40 (m, 4H), 3.07-3.04 (m, 2H),2.91-2.89 (m, 2H), 2.73-2.71 (m, 2H), 2.30- 2.20 (m, 2H), 1.73-1.65 (m,4H), 1.21-1.20 (m, 9H). 355

494 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 6.0 Hz), 7.76 (d, 2H, J = 8.8 Hz), 7.30 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.2 Hz), 5.97 (d, 1H, J = 4.2 Hz), 3.92 (br. s.,2H), 3.70 (br. s., 2H), 3.54 (br. s., 2H), 3.47 (br. s., 2H), 3.16-2.98(m, 3H), 2.47-2.43 (m, 2H), 2.36-2.26 (m, 1H), 2.16-2.07 (m, 2H),2.05-1.98 (m, 1H), 1.82- 1.78 (m, 1H), 1.03 (t, 3H, J = 7.2 Hz), 0.77-0.74 (m, 4H). 356

494 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (s, 1H), 8.16 (d, 1H, J= 1.6 Hz), 7.91 (d, 1H, J = 5.2 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.31 (d,2H, J = 8.4 Hz), 7.04 (d, 1H, J = 1.6 Hz), 6.12-5.84 (m, 1H), 5.99 (d,1H, J = 5.2 Hz), 3.79-3.78 (m, 2H), 3.55-3.45 (m, 4H), 3.37-3.31 (m,3H), 3.03-3.02 (m, 1H), 2.77-2.75 (m, 2H), 2.57- 2.53 (m, 4H), 2.25-2.17(m, 1H), 1.84-1.74 (m, 1H), 1.10-1.07 (m, 6H). 357

494 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.22 (d, 1H, J =Hz), 7.91 (d,1H, J = 5.6 Hz), 7.65- 7.59 (m, 2H), 7.33-7.30 (m, 1H), 7.06 (d, 1H, J =1.2 Hz), 5.97 (d, 1H, J = 5.6 Hz), 4.08 (q, 2H, J = 7.2 Hz), 3.61-3.59(m, 4H), 3.49-3.46 (m, 4H), 2.89-2.88 (m, 2H), 2.72-2.67 (m, 2H),2.24-2.20 (m, 2H), 1.73-1.65 (m, 4H), 1.21 (t, 3H, J = 7.2 Hz), 0.98 (d,6H, J = 6.4 Hz). 358

495 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.89 (d, J = 5.4Hz, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.31-7.16 (m, 2H), 6.99 (s, 1H), 5.98(d, J = 5.5 Hz, 1H), 4.77-4.64 (m, 1H), 4.63- 4.52 (m, 1H), 4.37-4.27(m, 1H), 4.25 (t, J = 4.0 Hz, 1H), 3.62 (s, 4H), 3.47 (t, J = 5.1 Hz,4H), 2.90 (s, 2H), 2.70 (d, J = 29.0 Hz, 1H), 2.24 (s, 2H), 1.88-1.54(m, 5H), 1.00 (d, J = 6.6 Hz, 6H). 359

495 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, 1H, J = 1.6 Hz),7.87 (d, 1H, J = 5.6 Hz), 7.66 (d, 2H, J = 8.4 Hz), 6.96-6.94 (m, 3H),6.20- 6.15 (m, 1H), 5.95 (d, 1H, J = 5.6 Hz), 3.92- 3.90 (m, 2H),3.75-3.65 (m, 2H), 3.51-3.44 (m, 4H), 3.15 (t, 4H, J = 4.8 Hz),2.83-2.74 (m, 2H), 2.68-2.66 (m, 4H), 2.02-1.98 (m, 1H), 0.78-0.72 (m,4H). 360

495 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 7.90 (d, 1H, J= 4.8 Hz), 7.57 (d, 2H, J = 10.8 Hz), 7.14 (s, 1H), 5.96 (d, 1H, J = 5.6Hz), 3.92 (br. s., 2H), 3.70 (br. s., 2H), 3.53 (br. s., 2H), 3.47 (br.s., 2H), 3.13 (s, 4H), 2.50 (br. s., 4H), 2.38 (q, 2H, J = 7.2 Hz),2.02-2.00 (m, 1H), 1.02 (t, 3H, J = 7.2 Hz), 0.78-0.75 (m, 4H). 361

495 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 2.0 Hz),7.87 (d, 1H, J = 5.6 Hz), 7.65 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.8Hz), 6.94-6.93 (m, 1H), 5.97 (d, 1H, J = 5.6 Hz), 4.00-3.85 (m, 1H),3.80-3.60 (m, 3H), 3.58- 3.40 (m, 4H), 3.30-3.24 (m, 4H), 3.23-3.20 (m,1H), 3.18-3.10 (m, 4H), 2.37 (q, 2H, J = 7.2 Hz), 2.00-1.90 (m, 2H),1.03 (t, 3H, J = 7.2 Hz). 362

495 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.94 (d, 1H, J= 5.6 Hz), 7.90 (d, 1H, J = 1.2 Hz), 6.83 (s, 1H), 7.76 (d, 2H, J = 12.8Hz), 6.01 (d, 1H, J = 5.6 Hz), 3.93-3.91 (m, 2H), 3.69-3.68 (m, 2H),2.55-2.54 (m, 2H), 3.51-3.50 (m, 2H), 3.25-3.22 (m, 4H), 2.48- 2.47 (m,4H), 2.37 (q, 2H, J = 7.2 Hz), 2.04- 2.00 (m, 1H), 1.04 (t, 3H, J = 7.2Hz), 0.78- 0.72 (m, 4H). 363

497 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.00 (s, 1H), 7.88 (d, 1H, J= 5.6 Hz), 7.75 (d, 1H, J = 8.8 Hz), 7.28 (t, 1H, J = 74 Hz), 6.96 (s,1H), 6.89 (d, 1H, J = 8.4 Hz), 6.76 (s, 1H), 5.96 (d, 1H, J = 5.6 Hz),3.91-3.90 (m, 2H), 3.69-3.67 (m, 2H), 3.52-3.46 (m, 4H), 3.24-3.20 (m,4H), 2.79-2.74 (m, 4H), 2.01-1.98 (m, 1H), 0.84- 0.73 (m, 4H). 364

497 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.77-3.68 (m,2H), 3.68-3.62 (m, 1H), 3.57-3.50 (m, 2H), 3.48-3.40 (m, 4H), 3.30- 3.20(m, 2H), 3.05-2.95 (m, 1H), 2.80-2.68 (m, 2H), 2.65-2.55 (m, 2H),2.50-2.42 (m, 3H), 2.40-2.35 (m, 1H), 2.25-2.15 (m, 1H), 1.80- 1.70 (m,1H), 1.10-1.00 (m, 6H). 365

497 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.2 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 1.2 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.97-3.93 (m,2H), 3.72-3.70 (m, 2H), 3.60-3.50 (m, 2H), 3.49-3.44 (m, 2H), 2.96- 2.92(m, 3H), 2.81-2.77 (m, 1H), 2.52-2.50 (m, 1H), 2.34-2.26 (m, 2H),2.15-2.05 (m, 1H), 1.82-1.75 (m, 2H), 1.71-1.61 (m, 2H), 1.50- 1.44 (m,1H), 1.38-1.34 (m, 1H), 1.03 (d, 6H, J = 6.8 Hz). 366

497 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.73 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.4Hz), 7.00 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 3.73-3.67 (m,2H), 3.67-3.64 (m, 1H), 3.54-3.50 (m, 2H), 3.45-3.39 (m, 4H), 3.27- 3.25(m, 2H), 3.01-2.96 (m, 1H), 2.75-2.71 (m, 2H), 2.66-2.63 (m, 2H),2.61-2.53 (m, 2H), 2.50-2.46 (m, 1H), 2.45-2.41 (m, 1H), 2.22- 2.19 (m,1H), 1.79-1.73 (m, 1H), 1.07-1.04 (m, 6H). 367

498 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.87 (d, 1H, J = 2.0 Hz), 7.82(d, 1H, J = 5.2 Hz), 7.55 (d, 2H, J = 8.8 Hz), 6.97 (d, 2H, J = 8.8 Hz),6.62 (d, 1H, J = 2.0 Hz), 5.82 (d, 1H, J = 5.2 Hz), 3.87-3.83 (m, 2H),3.62-3.58 (m, 1H), 3.57-3.54 (m, 2H), 3.43-3.41 (m, 4H), 3.29- 3.24 (m,4H), 3.22-3.14 (m, 1H), 2.82-2.74 (m, 2H), 2.66-2.62 (m, 4H), 2.61-2.55(m, 2H), 2.50 (q, 2H, J = 7.2 Hz), 1.15 (t, 3H, J = 7.2 Hz). 368

498 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 2.0 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0Hz), 6.98 (d, 1H, J = 1.2 Hz), 5.95 (d, 1H, J = 5.2 Hz), 4.21 (t, 2H, J= 8.8 Hz), 4.08 (dd, 2H, J = 8.0, 6.4 Hz), 3.80-3.70 (m, 1H), 3.50-3.40(m, 8H), 3.30-3.20 (m, 1H), 3.10-2.90 (m, 1H), 2.80-2.60 (m, 2H),2.45-2.35 (m, 2H), 2.30- 2.10 (m, 1H), 1.80-1.70 (m, 1H), 1.05 (t, 6H, J= 6.4 Hz). 369

498 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.92 (d, 1H, J = 1.6 Hz), 7.85(d, 1H, J = 5.2 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0 Hz),6.67 (d, 1H, J = 1.6 Hz), 5.84 (d, 1H, J = 5.2 Hz), 4.33-4.22 (m, 4H),3.62-3.56 (m, 4H), 3.51-3.47 (m, 4H), 3.50-3.40 (m, 2H), 3.33- 3.26 (m,1H), 3.10-3.00 (m, 1H), 2.79-2.69 (m, 1H), 2.60-2.49 (m, 2H), 2.41-2.30(m, 1H), 2.01-1.90 (m, 1H), 1.18 (d, 6H, J = 4.4 Hz). 370

498 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 2.0 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4Hz), 6.98 (d, 1H, J = 1.2 Hz), 5.94 (d, 1H, J = 5.6 Hz), 4.21 (t, 2H, J= 8.4 Hz), 4.08 (dd, 2H, J = 8.4, 6.0 Hz), 3.77-3.75 (m, 1H), 3.46-3.45(m, 8H), 2.99-2.95 (m, 2H), 2.49-2.44 (m, 1H), 2.34 (q, 2H, J = 7.2 Hz),1.97-1.92 (m, 2H), 1.76-1.70 (m, 2H), 1.68-1.63 (m, 2H), 1.01 (t, 3H, J= 7.2 Hz). 371

498 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.30 (s, 1H), 8.08 (d, 1H, J= 1.6 Hz), 7.87 (d, 1H, J = 5.6 Hz), 7.67 (d, 2H, J = 8.4 Hz), 6.96 (d,2H, J = 8.4 Hz), 6.94 (d, 1H, J = 1.6 Hz), 5.95 (d, 1H, J = 5.6 Hz),3.75-3.67 (m, 2H), 3.67-3.60 (m, 2H), 3.50-3.42 (m, 2H), 3.42-3.35 (m,2H), 3.22-3.14 (m, 4H), 3.06-2.94 (m, 4H), 2.76- 2.64 (m, 2H), 2.10-2.00(m, 2H), 1.78-1.68 (m, 2H), 1.66-1.50 (m, 2H), 1.48-1.34 (m, 2H). 372

498 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.0Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 3.92-3.86 (m,2H), 3.72-3.68 (m, 2H), 3.54-3.49 (m, 2H), 3.48-3.43 (m, 2H), 3.31- 3.27(m, 1H), 2.94-2.91 (m, 1H), 2.68-2.62 (m, 2H), 2.46-2.42 (m, 2H),2.26-2.24 (m, 1H), 2.16-2.10 (m, 1H), 1.98-1.92 (m, 2H), 1.80- 1.66 (m,6H), 1.28-1.22 (m, 2H), 1.06 (t, 3H, J = 7.2 Hz), 0.99-0.95 (m, 1H),0.65-0.60 (m, 1H). 373

499 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.09 (s, 1H), 7.87 (d, 1H, J= 5.6 Hz), 7.67 (d, 2H, J = 8.4 Hz), 6.99 (d, 2H, J = 8.4 Hz), 6.95 (s,1H), 5.96 (d, 1H, J = 5.6 Hz), 3.92 (br. s., 2H), 3.69-3.63 (m, 3H),3.51-3.45 (m, 6H), 3.04- 3.01 (m, 1H), 2.94-2.89 (m, 1H), 2.86-2.79 (m,1H), 2.76-2.66 (m, 2H), 2.06-2.00 (m, 1H), 0.78-0.71 (m, 4H). 374

499 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.34 (s, 1H), 8.07 (d, 1H, J= 1.6 Hz), 7.87 (d, 1H, J = 5.2 Hz), 7.64 (d, 2H, J = 8.8 Hz), 7.01 (d,2H, J = 8.8 Hz), 6.95 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.2 Hz),4.71-4.68 (m, 1H), 3.92 (br. s., 2H), 3.71 (br. s., 2H), 3.53-3.35 (m,4H), 3.28-3.09 (m, 3H), 3.03-2.96 (m, 2H), 2.74- 2.67 (m, 1H). 375

499 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.27 (s, 1H), 8.17 (d, 1H, J= 1.6 Hz), 7.90 (d, 1H, J = 5.2 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.33 (d,2H, J = 8.4 Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz),4.50-4.30 (m, 1H), 3.95-3.85 (m, 1H), 3.79-3.75 (m, 2H), 3.70-3.65 (m,2H), 3.60-3.55 (m, 2H), 3.52-3.45 (m, 2H), 3.42- 3.38 (m, 2H), 3.00-2.90(m, 1H), 2.80-2.71 (m, 2H), 2.70-2.65 (m, 2H), 2.10-2.00 (m, 2H),1.80-1.68 (m, 2H), 1.65-1.50 (m, 2H), 1.48- 1.30 (m, 2H). 376

499 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 8.06 (d, 1H, J= 1.6 Hz), 7.86 (d, 1H, J = 5.6 Hz), 7.64 (d, 2H, J = 8.8 Hz), 6.96 (d,2H, J = 8.8 Hz), 6.91 (d, 1H, J = 1.6 Hz), 5.94 (d, 1H, J = 5.6 Hz),4.22 (t, 2H, J = 8.8 Hz), 4.09 (dd, 2H, J = 8.0, 6.0 Hz), 3.78-3.73 (m,1H), 2.47-2.46 (m, 4H), 2.45-2.44 (m, 4H), 3.18- 3.16 (m, 4H), 2.55-2.53(m, 4H), 2.40 (q, 2H, J = 7.2 Hz), 1.05 (t, 3H, J = 7.2 Hz). 377

500 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.30 (s, 1H), 8.14 (d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.25 (d,2H, J = 8.4 Hz), 7.07 (t, 1H, J = 5.6 Hz), 7.01 (d, 1H, J = 1.6 Hz),5.98 (d, 1H, J = 5.6 Hz), 3.58- 3.52 (m, 4H), 3.48-3.42 (m, 4H),3.33-3.24 (m, 2H), 3.03-2.98 (m, 2H), 2.90-2.85 (m, 1H), 2.69-2.64 (m,2H), 2.55-2.50 (m, 1H), 2.43- 2.39 (m, 2H), 1.84-1.75 (m, 2H), 1.74-1.68(m, 2H), 1.06 (d, 6H, J = 6.4 Hz). 378

501 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.2 Hz), 5.97 (d, 1H, J = 5.2 Hz), 5.30-5.00 (m,1H), 3.80-3.70 (m, 2H), 3.70-3.60 (m, 2H), 3.54-3.45 (m, 2H), 3.42- 3.33(m, 4H), 3.18-3.10 (m, 1H), 3.08-3.02 (m, 1H), 2.80-2.60 (m, 3H),2.10-1.98 (m, 2H), 1.80-1.66 (m, 2H), 1.62-1.50 (m, 2H), 1.46- 1.30 (m,2H). 379

501 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J = 8.0Hz), 6.70 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.45-3.44 (m,4H), 3.35-3.33 (m, 4H), 3.16-3.13 (m, 4H), 2.99-2.96 (m, 2H), 2.48- 2.42(m, 1H), 2.34 (q, 2H, J = 7.2 Hz), 1.98- 1.92 (m, 2H), 1.76-1.71 (m,2H), 1.70-1.60 (m, 2H), 1.60-1.50 (m, 2H), 1.50-1.40 (m, 4H), 1.02 (t,3H, J = 7.2 Hz). 380

502 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 1.8 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H),6.97 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 5.97 (d, J = 5.5 Hz,1H), 4.12 (h, J = 8.3 Hz, 1H), 3.52 (dd, J = 6.9, 3.3 Hz, 4H), 3.42 (dd,mJ = 6.7, 3.5 Hz, 4H), 2.88 (d, J = 10.6 Hz, 2H), 2.71 (p, J = 6.6 Hz,1H), 2.27-2.17 (m, 2H), 2.12 (qt, J = 7.7, 2.6 Hz, 2H), 1.93 (pd, J =9.1, 2.7 Hz, 2H), 1.76 (d, J = 12.3 Hz, 2H), 1.69- 1.47 (m, 4H), 0.99(d, J = 6.5 Hz, 6H). 381

502 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0Hz), 7.00 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 5.11 (d, 1H, J= 6.0 Hz), 4.15-4.08 (m, 1H), 3.72-3.65 (m, 2H), 3.60-3.50 (m, 2H),3.48-3.40 (m, 4H), 3.10-2.99 (m, 1H), 3.85- 3.78 (m, 2H), 3.78-3.69 (m,2H), 2.44-2.39 (m, 2H), 2.20-2.10 (m, 2H), 2.09-2.03 (m, 2H), 1.85-1.79(m, 1H), 1.77-1.70 (m, 1H), 1.60- 1.42 (m, 2H), 0.97 (dd, 6H, J = 6.4,3.2 Hz). 382

502 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (s, 1H), 7.88 (d, 1H, J= 4.4 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4 Hz), 6.93 (s,1H), 5.97-5.93 (m, 1H), 5.10 (d, 1H, J = 2.0 Hz), 4.70-4.30 (m, 1H),4.12-4.08 (m, 1H), 3.89- 3.86 (m, 2H), 3.60-3.50 (m, 1H), 3.21-3.05 (m,2H), 3.05-3.00 (m, 1H), 3.00-2.96 (m, 2H), 2.49-2.48 (m, 1H), 2.37-2.35(m, 4H), 2.10- 2.00 (m, 2H), 2.00-1.94 (m, 2H), 1.78-1.75 (m, 2H),1.70-1.67 (m, 2H), 1.37-1.32 (m, 1H)m 1.27-1.21 (m, 2H), 1.03 (t, 3H, J= 7.2 Hz). 383

503 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.7 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H),6.99 (d, J = 1.9 Hz, 1H), 5.95 (d, J = 5.5 Hz, 1H), 4.97 (s, 1H), 3.63(dt, J = 27.9, 4.8 Hz, 4H), 3.43 (q, J = 5.9, 4.1 Hz, 4H), 2.98 (d, J =11.0 Hz, 2H), 2.89 (q, J = 8.8 Hz, 1H), 2.34 (q, J = 7.2 Hz, 2H), 2.19(t, J = 10.1 Hz, 2H), 2.08 (td, J = 8.5, 2.6 Hz, 2H), 2.03-1.88 (m, 2H),1.75 (d, J = 11.3 Hz, 2H), 1.65 (qd, J = 12.3, 3.5 Hz, 2H), 1.28 (s,3H), 1.02 (t, J = 7.2 Hz, 3H). 384

503 385

502 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz),k 7.27 (d, 2H, J =8.0 Hz), 7.00 (d, 1H, J = 1.2 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.10 (d,1H, J = 6.0 Hz), 4.13-4.11 (m, 1H), 3.70-3.69 (m, 2H), 3.55-3.54 (m,2H), 3.45-3.43 (m, 4H), 3.24-3.22 (m, 1H), 2.82- 2.77 (m, 2H), 2.76-2.67(m, 2H), 2.44-2.38 (m, 2H), 2.20-2.14 (m, 2H), 2.10-2.03 (m, 2H),1.81-1.79 (m, 1H), 1.72-1.70 (m, 1H), 1.59- 1.50 (m, 1H), 1.48-1.40 (m,1H), 0.99-0.96 (m, 6H). 386

502 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.25 (s, 1H), 8.15 (d, 1H, J= 1.6 Hz), 7.91 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.25 (d,2H, J = 8.4 Hz), 7.00 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz),3.89 (d, 2H, J = 6.8 Hz), 3.65- 3.59 (m, 4H), 3.50-3.40 (m, 4H),2.97-2.93 (m, 2H), 2.82-2.78 (m, 1H), 2.52-2.50 (m, 1H), 2.35-2.28 (m,2H), 1.82-1.77 (m, 2H), 1.70- 1.64 (m, 2H), 1.14-1.11 (m, 1H), 1.03 (d,6H, J = 6.8 Hz), 0.54-0.51 (m, 2H), 0.30-0.27 (m, 2H). 387

502 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz)_,7.90 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 5.11 (d, 1H, J= 5.6 Hz), 4.14-4.11 (m, 1H), 3.69-3.68 n(m, 2H), 3.55-3.54 (m, 2H),3.46-3.44 (m, 4H), 3.22-3.21 (m, 1H), 2.81- 2.75 (m, 2H), 2.74-2.68 (m,3H), 2.43-2.38 (m, 2H), 2.19-2.10 (m, 2H), 2.08-2.01 (m, 2H), 1.72-17.71(m, 1H), 1.70-1.69 (m, 1H), 1.60- 1.40 (m, 2H), 0.98-0.96 (m, 6H). 388

502 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.22 (s, 1H), 8.19 (d, 1H, J= 1.6 Hz), 7.91 (d, 1H, J = 5.2 Hz), 7.80 (d, 2H, J = 8.4 Hz), 7.48 (d,2H, J = 8.4 Hz), 7.06 (s, 1H), 5.98 (d, 1H, J = 5.2 Hz), 3.94-3.91 (m,2H), 3.74-3.70 (m, 2H), 3.60-3.52 (m, 2H), 3.50-3.45 (m, 2H), 2.92 (s,3H), 2.92-2.81 (m, 3H), 2.60-2.50 (m, 1H), 2.03-2.01 (m, 1H), 1.85-1.80(m, 2H). 1.80- 1.75 (m, 1H), 1.45-1.40 (m, 1H), 1.04 (d, 6H, J = 6.4Hz), 0.78-0.74 (m, 4H). 389

502 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.19 (s, 1H), 7.91 (d, 1H, J= 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4 Hz), 7.06 (s,1H), 5.98 (d, 1H, J = 5.6 Hz), 4.01-3.91 (m, 2H), 3.76-3.69 (m, 2H),3.55-3.50 (m, 2H), 3.50- 3.45 (m, 2H), 2.89 (s, 3H), 2.71-2.69 (m, 1H),2.61-2.59 (m, 2H), 2.47-2.45 (m, 2H), 2.03- 1.96 (m, 2H), 1.88-1.81 (m,2H), 1.00 (d, 6H, J = 6.0 Hz), 0.78-0.75 (m, 4H). 390

503 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.74- 7.72 (m, 2H), 6.99-6.96 (m, 3H), 5.97(d, 1H, J = 5.6 Hz), 4.11 (t, 2H, J = 6.0 Hz), 3.92 (br. s., 2H), 3.70(br. s., 2H), 3.53-3.37 (m, 6H), 2.71 (t, 2H, J = 5.6 Hz), 2.60-2.48 (m,4H), 2.43- 2.36 (m, 4H), 2.04-2.01 (m, 1H), 1.02 (t, 2H, J = 7.2 Hz),0.79-0.73 (m, 4H). 391

503 1H-NMR (H-NMR (400 MHz, CDCl3) δ 7.88 (d, 1H, J = 1.6 Hz), 7.83 (d,1H, J = 5.2 Hz), 7.56 (d, 2H, J = 8.4 Hz), 6.99 (d, 2H, J = 8.4 Hz),6.63 (d, 1H, J = 1.6 Hz), 5.83 (d, 1H, J = 5.2 Hz), 3.93-3.83 (m, 2H),3.72-3.62 (m, 2H), 3.51- 3.39 (m, 4H), 3.33-3.22 (m, 4H), 2.99-2.98 (m,1H), 2.71-2.60 (m, 4H), 2.51 (q, 2H, J = 7.2 Hz), 2.44-2.32 (m, 4H),1.42 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H). 392

503 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.27 (s, 1H), 8.14 ()d, 1H, J= 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.73 (d, 2H, J = 8.4 Hz), 7.25 (d,2H, J = 8.4 Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz),3.50-3.41 (m, 4H), 3.40-3.30 (m, 4H), 3.18 (q, 4H, J = 6.8 Hz),3.00-2.95 (m, 2H), 2.85 (heptet, 1H, J = 6.8 Hz), 2.52- 2.50 (m, 1H),2.40-2.31 (m, 2H), 1.82-1.78 (m, 2H), 1.75-1.66 (m, 2H), 1.08 (t, 6H, J= 6.8 Hz), 1.04 (d, 6H, J = 6.8 Hz). 393

503 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.12 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.2 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.24 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 6.25 (d, 1H, J = 8.0 Hz), 5.97 (d, 1H, J= 5.6 Hz), 3.66-3.55 (m, 1H), 3.54-3.48 (m, 4H), 3.46-3.38 (m, 4H),2.92-2.82 (m, 2H), 2.74-2.64 (m, 1H), 2.46- 2.40 (m, 1H), 2.26-2.14 (m,2H), 1.80-1.70 (m, 2H), 1.68-1.54 (m, 2H), 1.50-1.30 (m, 2H), 1.04 (d,3H, J = 6.8 Hz), 0.98 (d, 6H, J = 6.8 Hz), 0.83 (t, 3H, J = 7.2 Hz). 394

503 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.12 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.24 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 6.25 (d, 1H, J = 8.0 Hz), 5.97 (d, 1H, J= 5.6 Hz), 3.68-3.55 (m, 1H), 3.54-3.48 (m, 4H), 3.46-3.38 (m, 4H),2.92-2.82 (m, 2H), 2.74-2.64 (m, 1H), 2.46- 2.40 (m, 1H), 2.26-2.14 (m,2H), 1.80-1.70 (m, 2H), 1.68-1.54 (m, 2H), 1.50-1.30 (m, 2H), 1.04 (d,3H, J = 6.4 Hz), 0.98 (d, 6H, J = 6.4 Hz), 0.83 (t, 3H, J = 7.2 Hz). 395

504 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 1.7 Hz, 1H), 7.87(d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H),6.97 (d, J = 1.9 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 5.90 (s, 1H), 3.45(ddd, J = 28.3, 7.6, 4.0 Hz, 9H), 2.88 (d, J = 10.8 Hz, 2H), 2./80-2.57(m, 1H), 2.21 (t, J = 11.1 Hz, 2H), 1.76 (d, J = 12.4 Hz, 2H), 1.70-1.49(m, 2H), 1.27 (s, 9H), 0.99 (d, J = 6.5 Hz, 6H). 396

504 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.12 (d, J = 1.7Hz), 7.88 (d, J = 5.4 Hz, 1H), 7.76-7.67 (m, 2H), 7.28-7.19 (m, 2H),6.98 (d, J = 1.9 Hz, 1H), 6.56 (t, J = 5.5 Hz, 1H), 5.97 (d, J = 5.5 Hz,1H), 3.56-3.47 (m, 4H), 3.42 (dd, J = 6.8, 3.4 Hz, 4H), 3.09-3.00 (m,2H), 2.95 (d, J = 11.0 Hz, 2H), 2.81 (p, J = 6.5 Hz, 1H), 2.32 (dd, J =12.6, 10.1 Hz, 2H), 1.79 (d, J = 12.4 Hz, 2H), 1.74-1.59 (m, 2H),1.46-1.34 (m, 2H), 1.27 (h, J = 7.2 Hz, 2H), 1.02 (d, J = 6.6 Hz, 5H),0.87 (t, J = 3.7 Hz, 3H). 397

504 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (br. s., 1H), 8.06 (d,1H, J = 1.6 Hz), 7.86 (d, 1H, J = 5.2 Hz), 7.65 (d, 2H, J = 8.4 Hz),6.95 (d, 2H, J = 8.4 Hz), 6.91 (d, 1H, J = 1.6 Hz), 5.94 (d, 1H, J = 5.2Hz), 4.15-4.12 (m, 3H), 3.78-3.75 (m, 2H), 3.46-3.44 (m, 8H), 3.20 (s,3H), 3.16-3.15 (m, 4H), 2.55-2.54 (m, 4H), 2.41 (q, 2H, J = 7.2 Hz),1.05 (t, 3H, J = 7.2 Hz). 398

505 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.16 (d, J = 1.7Hz, 1H), 7.90 (d, J = 5.4 Hz, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.25 (d, J= 8.1 Hz, 2H), 7.01 (d, J = 1.8 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 3.83(d, J = 6.5 Hz, 2H), 3.61 (br. s, 4H), 3.52-3.41 (m, 7H), 3.15-3.01 (m,2H), 2.87 (p, J = 9.4, 8.5 Hz, 1H), 2.03 (t, J = 9.3 Hz, 4H), 1.89(hept, J = 6.8 Hz, 1H), 1.29 (d, J = 6.6 Hz, 6H), 0.91 (d, J = 6.7 Hz,6H) 399

505 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 7.98 (d, 1H, J = 1.2 Hz), 7.85(d, 1H, J = 5.2 Hz), 7.74 (d, 1H, J = 8.4 Hz), 7.45 (d, 1H, J = 8.4 Hz),6.92 (d, 1H, J = 1.2 Hz), 6.00 (d, 1H, J = 5.2 Hz), 3.67-3.64 (m, 4H),3.56-3.54 (m, 4H), 3.24 (q, 2H, J = 7.2 Hz), 3.00 (s, 3H), 2.87- 2.82(m, 3H), 2.77-2.71 (m, 2H), 2.20-2.16 (m, 2H), 2.08-2.02 (m, 2H), 1.17(d, 6H, J = 6.4 Hz), 1.15 (t, 3H, J = 7.2 Hz). 400

505 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.90 (d, 1H, J= 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.48 (d, 2H, J = 8.4 Hz), 7.03 (d,1H, J = 1.2 Hz), 6.62 (t, 1H, J = 5.6 Hz), 5.99 (d, 1H, J = 5.6 Hz),3.53-3.51 (m, 4H), 3.45- 3.43 (m, 4H), 3.33-3.30 (m, 1H), 3.20-3.10 (m,2H), 2.92 (s, 3H), 2.80-2.74 (m, 2H), 2.72-2.60 (m, 1H), 2.50-2.40 (m,2H), 1.83-1.71 (m, 3H), 1.06-1.01 (m, 9H). 401

507 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.7 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H),6.99 (d, J = 1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.21-4.10 (m, 2H),3.68-3.57 (m, 4H), 3.57- 3.50 (m, 2H), 3.50-3.41 (m, 4H), 3.28 (s, 3H),2.87 (s, 2H), 2.68 (d, J = 17.6 Hz, 1H), 2.21 (s, 2H), 1.75 (s, 2H),1.62 (d, J = 13.0 Hz, 2H), 0.99 (d, J = 6.4 Hz, 6H). 402

509 1H-NMR (H-NMR (500 MHz, DMSO-d6) δ ppm 8.07 (s, 1H), 7.88 (d, 1H, J= 5.5 Hz), 7.65 (d, 2H, J = 8.0 Hz), 6.97-6.93 (m, 3H), 5.96 (d, 1H, J =5.5 Hz), 3.72-3.71 (m, 2H), 3.63-3.62 (m, 2H), 3.47-3.46 (m, 4H),3.40-3.39 (m, 4H), 3.17- 3.16 (m, 4H), 2.86-2.80 (m, 4H), 2.39-2.37 (m,2H), 1.24 (s, 1H), 1.04 (t, 3H, J = 7.5 Hz). 403

509 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.11 (s, 1H), 7.92 (t, 1H, J= 6.0 Hz), 7.60 (d, 2H, J = 8.4 Hz), 6.97 (d, 2H, J = 8.4 Hz), 6.86-6.83(m, 1H), 6.51 (td, 1H, J = 56 Hz, 5.6 Hz), 6.04 (dd, 1H, J = 13.6 Hz,5.2 Hz), 4.92-4.90 (m, 1H), 4.43-4.34 (m, 1H), 4.16-4.12 (m, 1H),3.89-3.85 (m, 1H), 3.30-3.25 (m, 4H), 3.25- 3.20 (m, 2H), 3.19-3.15 (m,4H), 2.90-2.80 (m, 1H), 2.38 (q, 2H, J = 7.2 Hz), 2.10-2.05 (m, 1H),1.04 (t, 3H, J = 7.2 Hz), 0.86-0.75 (m, 4H). 404

511 1H-NMR (H-NMR (400 MHz, CDCl3) δ 7.84 (d, 1H, J = 1.6 Hz), 7.82 (d,1H, J = 5.6 Hz), 7.50 (d, 2H, J = 8.4 Hz), 6.60 (d, 1H, J = 1.6 Hz),6.50 (d, 2H, J = 8.4 Hz), 5.81 (d, 2H, J = 6.0 Hz), 4.33-4.22 (m, 4H),3.98 (s, 4H), 3.65-3.56 (m, 4H), 3.51-3.48 (m, 1H), 3.45-3.38 (m, 4H),3.36 (s, 4H), 2.46 (q, 2H, J = 7.2 Hz), 0.98 (t, 3H, J = 7.2 Hz). 405

511 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J = 8.0Hz) 7.00 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.2 Hz), 3.68-3.67 (m,3H), 3.64-3.62 (m, 1H), 3.53-3.52 (m, 2H), 3.45-3.44 (m, 4H), 3.32- 3.29(m, 2H), 3.28-3.27 (m, 3H), 2.62-2.60 (m, 3H), 2.49-2.46 (m, 2H),1.90-1.80 (m, 4H), 1.16-1.15 (m, 6H). 406

511 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 7.98 (d, 1H, J = 1.6 Hz), 7.85(d, 1H, J = 5.2 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.36 (d, 2H, J = 8.4 Hz),6.91 (d, 1H, J = 5.2 Hz), 5.97 (d, 1H, J = 5.2 Hz), 4.12-4.06 (m, 2H),3.92-3.85 (m, 1H), 3.84-3.78 (m, 4H), 3.66-3.60 (m, 2H), 3.58- 3.53 (m,2H), 3.52-3.47 (m, 2H), 2.98-2.90 (m, 1H), 2.82-2.74 (m, 1H), 2.68-2.60(m, 1H), 2.20-2.14 (m, 2H), 1.90-1.84 (m, 2H), 1.74- 1.62 (m, 2H),1.60-1.48 (m, 2H), 1.12 (d, 6H, J = 6.4 Hz). 407

511 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.33 (br.s. 1H)), 8.15 (s,1H), 7.90 (d, 1H, J = 4.8 Hz), 7.73 (d, 2H, J = 7.6 Hz), 7.27 (d, 2H, J= 7.6 Hz), 6.96 (s, m1H), 5.97 (s, 1H), 4.66-4.62 (m, 1H), 4.22-4.16 (m,1H), 3.98-3.88 (m, 2H), 3.42-3.16 (m, 2H), 3.08-2.98 (m, 2H), 2.96- 2.84(m, 2H), 2.62-2.52 (m, 1H), 2.46-2.40 (m, 2H), 2.12-2.06 (m, 1H),1.88-1.72 (m, 4H), 1.50-1.40 (m, 3H), 1.32-1.24 (m, 3H), 1.08 (d, 6H, J= 5.2 Hz). 408

511 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (s, 1H), 7.90 (d, 1H, J= 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0 Hz), 6.99 (s,1H), 5.97 (d, 1H, J = 5.6 Hz), 3.69-3.67 (m, 2H), 3.64-3.60 (m, 1H),3.54-3.53 (m, 2H), 3.45- 3.43 (m, 4H), 3.32-3.30 (m, 1H), 2.80-2.78 (m,2H), 2.72-2.71 (m, 2H), 2.63-2.61 (m, 2H), 2.52-2.51 (m, 1H), 2.46-2.45(m, 1H), 2.19- 2.11 (m, 2H), 1.83-1.80 (m, 1H), 1.74-1.71 (m, 1H),1.58-1.50 (m, 1H), 1.49-1.42 (m, 1H), 0.98-0.96 (m, 6H). 409

511 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0Hz), 7.00 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 3.75-3.69 (m,2H), 3.70-3.67 (m, 1H), 3.54-3.53 (m, 2H), 3.45-3.33 (m, 4H), 3.31- 3.28(m, 1H), 2.81-2.79 (m, 2H), 2.74-2.70 (m, 2H), 2.66-2.63 (m, 2H),2.50-2.467 (m, 2H), 2.19-2.09 (m, 2H), 1.82-1.81 (m, 1H), 1.72- 1.71 (m,1H), 1.56-1.50 (m, 1H), 1.50-1.42 (m, 1H), 0.98-0.96 (m, 6H). 410

512 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.92 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.60 (d, 2H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.0Hz), 6.68 (d, 1H, J = 1.6 Hz), 5.87 (d, 1H, J = 5.6 Hz), 3.92-3.91 (m,4H), 3.47-3.45 (m, 4H), 3.44-3.43 (m, 1H), 3.18-3.17 (m, 1H), 2.96- 2.94(m, 1H), 2.68-2.67 (m, 2H), 2.53-2.52 (m, 2H), 2.37-2.36 (m, 1H),1.96-1.94 (m, 1H), 1.39-1.37 (m, 2H), 1.26-1.25 (m, 2H), 1.21- 1.16 (m,3H). 411

512 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (s, 1H), 8.15 (s, 1H),7.89 (d, 1H, J = 5.2 Hz), 7.73 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 6.99 (s, 1H), 5.95 (d, 1H, J = 5.2 Hz), 4.24-4.19 (m, 2H),4.11-4.01 (m, 2H), 3.77-3.74 (m, 1H), 2.89-2.84 (m, 4H), 2.41-2.37 (m,2H), 1.85-1.41 (m, 4H), 1.03-1.00 (m, 6H). 412

512 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (br. s., 1H), 8.15 (d,1H, J = 1.6 Hz), 7.89 (d, 1H, J = 5.6 Hz), 7.70 (d, 2H, J = 8.0 Hz),7.27 (d, 2H, J = 8.0 Hz), 6.90 (d, 1H, J = 1.6 Hz), 5.95 (d, 1H, J = 5.6Hz), 4.23-4.20 (m, 2H), 4.19-4.16 (m, 1H), 4.10-4.06 (m, 2H), 3.86- 3.83(m, 2H), 3.75-3.74 (m, 1H), 3.64-3.63 (m, 1H), 3.35-3.34 (m, 2H),3.16-3.03 (m, 2H), 3.01-2.99 (m, 1H), 2.39 (q, 2H, J = 7.2 Hz),2.01-1.98 (m, 2H), 1.79-1.74 (m, 2H), 1.72- 1.65 (m, 2H), 1.31 (d, 3H, J= 6.4 Hz), 1.04 (t, 3H, J = 7.2 Hz). 413

512 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (s, 1H), 7.86 (d, 1H, J= 5.6 Hz), 7.64 (d, 2H, J = 8.4 Hz), 6.93 (d, 2H, J = 8.4 Hz), 6.92-6.90(m, 1H), 5.94 (d, 1H, J = 5.6 Hz), 3.70-3.60 (m, 3H), 3.55-3.48 (m, 2H),3.45-3.38 (m, 4H), 3.30-3.22 (m, 1H), 3.17-3.08 (m, 4H), 2.70- 2.60 (m,1H), 2.58-2.54 (m, 6H), 2.48-2.42 (m, 2H), 1.00 (d, 6H, J = 6.4 Hz). 414

512 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4Hz), 7.00 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 3.90-3.60 (m,4H), 3.55-3.45 (m, 4H), 2.91-2.86 (m, 2H), 2.71 (heptet, 1H, J = 6.8Hz), 2.50-2.46 (m, 1H), 2.26-2.20 (m, 2H), 1.80-1.75 (m, 2H), 1.69-1.56(m, 2H), 1.24- 1.20 (m, 1H), 1.00 (d, 6H, J = 6.8 Hz), 0.78- 0.74 (m,2H), 0.53-0.50 (m, 2H), 0.48-0.43 (m, 2H), 0.15-0.11 (m, 2H). 415

515 1H-NMR (H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 1.8 Hz, 1H),7.85 (d, J = 5.3 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 8.0 Hz,3H), 6.69 (d, J = 1.9 Hz, 1H), 5.85 (d, J = 5.4 Hz, 1H), 3.86 (d, J =26.3 Hz, 5H), 3.49 (d, J = 31.7 Hz, 5H), 3.15 (s, 3H), 2.56 (td, J =15.0, 5.8 Hz, 3H), 2.34 (ddd, J = 33.9, 16.5, 9.0 Hz, 1H), 2.17-2.06 (m,7H), 1.89 (bs, 3H), 1.24 (d, J = 5.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 4H).416

516 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.88 (d, J = 5.4Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.28 (dd, J = 24.1, 7.9 Hz, 3H), 6.98(s, 1H), 6.36 (d, J = 7.0 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 5.75 (s,1H), 3.93 (p, J = 7.1 Hz, 1H), 3.60-3.40 (m, 10H), 2.11-1.72 (m, 2H),1.63 (q, J = 6.6, 6.2 Hz, 2H), 1.44 (ddt, J = 27.1, 11.9, 5.6 Hz, 4H),1.33-0.90 (m, 12H). 417

516 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.29 (br. s., 1H), 8.06 (d,1H, J = 1.6 Hz), 7.87 (d, 1H, J = 5.2 Hz), 7.65 (d, 2H, J = 8.8 Hz),6.95 (d, 2H, J = 8.8 Hz), 6.90 (d, 1H, J = 1.6 Hz), 5.94 (d, 1H, J = 5.2Hz), 4.66-4.42 (m, 4H), 4.11-4.03 (m, 4H), 3.49-3.45 (m, 4H), 3.44- 3.40(m, 4H), 3.17-3.11 (m, 4H), 2.53-2.50 (m, 4H), 2.38 (q, 2H, J = 7.2 Hz),1.04 (t, 3H, J = 7.2 Hz). 418

516 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.2 Hz), 4.58 (d, 1H, J= 4.0 Hz), 3.80-3.70 (m, 2H), 3.70-3.60 (m, 2H), 3.55-3.47 (m, 2H),3.47-3.40 (m, 2H), 3.39-3.35 (m, 1H), 3.30- 3.20 (m, 1H), 3.05-2.95 (m,1H), 2.80-2.60 (m, 2H), 2.58-2.51 (m, 1H), 2.45-2.30 (m, 2H), 2.28-2.10(m, 1H), 1.90-1.81 (m, 2H), 1.80- 1.75 (m, 1H), 1.70-1.60 (m, 2H),1.50-1.30 (m, 2H), 1.25-1.10 (m, 2H), 1.08-1.00 (m, 6H). 419

516 1H-NMR (H-NMR (400 MHz, CDCl3) δ 7.93 (d, 1H, J = 2.0 Hz), 7.86 (d,1H, J = 5.2 Hz), 7.61 (d, 2H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.0 Hz),6.69 (d, 1H, J = 1.6 Hz), 5.85 (d, 1H, J = 5.6 Hz), 3.92-3.82 (m, 2H),3.80-3.70 (m, 2H), 3.69-3.65 (m, 1H), 3.56-3.45 (m, 3H), 3.44- 3.41 (m,2H), 3.40-3.38 (m, 1H), 3.24-3.12 (m, 1H), 2.99-2.87 (m, 1H), 2.80-2.66(m, 2H), 2.53-2.36 (m, 2H), 2.14-2.00 (m, 4H), 1.90- 1.78 (m, 2H),1.74-1.71 (m, 1H), 1.39-1.34 (m, 2H), 1.27 (d, 6H, J = 6.4 Hz). 420

517 1H-NMR (H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.3 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.2 Hz,2H), 6.67 (d, J = 1.8 Hz, 1H), 5.83 (d, J = 5.3 Hz, 1H), 4.12 (q, J =7.1 Hz, 2H), 3.87 (d, J = 5.6 Hz, 2H), 3.66 (s, 2H), 3.45 (s, 2H), 3.03(d, J = 11.2 Hz, 2H), 2.98-2.86 (m, 1H), 2.78 (p, J = 6.5 Hz, 1H),2.59-2.44 (m, 2H), 2.44-2.35 (m, 4H), 2.27 (t, J = 11.0 Hz, 2H),1.94-1.77 (m, 4H), 1.25 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.6 Hz, 6H).421

517 1H-NMR (H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.3 Hz, 1H), 7.61- 7.49 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H),6.67 (d, J = 1.9 Hz, 1H), 5.83 (d, J = 5.4 Hz, 1H), 4.11 (q, J = 7.1 Hz,1H), 3.87 (t, J = 5.1 Hz, 2H), 3.73-3.62 (m, 3H), 3.51-3.36 (m, 2H),3.18 (s, 2H), 2.93 (p, J = 8.1 Hz, 1H), 2.58 (s, 2H), 2.52-2.29 (m, 5H),1.94 (d, J = 12.9 Hz, 2H), 1.41 (s, 3H), 1.24 (dt, J = 10.8, 6.8 Hz,10H). 422

517 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 6.0 Hz), 7.64 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.8Hz), 6.93 (d, 1H, J = 1.6 Hz), 5.94 (d, 1H, J = 5.6 Hz), 4.57 (d, 1H, J= 4.4 Hz), 3.73-3.70 (m, 2H), 3.70-3.64 (m, 2H), 3.48-3.45 (m, 2H),3.44-3.38 (m, 2H), 3.17-3.13 (m, 4H), 2.53- 2.58 (m, 4H), 1.86-1.83 (m,2H), 1.70-1.66 (m, 2H), 1.56-1.53 (m, 1H), 1.43-1.16 (m, 5H), 1.06-1.04(m, 3H), 0.93 (t, 3H, J = 7.2 Hz). 423

517 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.2 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J = 8.0Hz), 6.99 (d, 1H, J = 1.2 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.72 (d, 1H, J= 3.6 Hz), 3.65-3.60 (m, 1H), 3.52-3.49 (m, 2H), 3.49-3.43 (m, 4H),3.40-3.35 (m, 4H), 3.40-3.24 (m, 2H), 3.08- 2.98 (m, 2H), 2.93-2.87 (m,2H), 2.41 (q, 2H, J = 7.2 Hz), 2.07-2.01 (m, 2H), 1.78-1.66 (m, 6H),1.33 (q, 2H, J = 10.4 Hz), 1.03 (t, 3H, J = 7.2 Hz). 424

518 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.12 (d, J = 1.7Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.76-7.65 (m, 2H), 7.29-7.20 (m, 2H),6.98 (d, J = 1.9 Hz, 1H), 6.57 (t, J = 5.5 Hz, 1H), 5.97 (d, J = 5.5 Hz,1H), 3.51 (dd, J = 6.9, 3.3 Hz, 4H), 3.42 (dd, J = 6.7, 3.5 Hz, 4H),3.03 (q, J = 6.6 Hz, 2H), 2.94 (d, J = 11.0 Hz, 2H), 2.79 (p, J = 6.6Hz, 1H), 2.30 (dd, J = 12.6, 10.0 Hz, 2H), 1.78 (d, J = 12.5 Hz, 2H),1.66 (tt, J = 12.8, 6.4 Hz, 2H), 1.42 (p, J = 7.3 Hz, 2H), 1.26 (dtd, J= 14.3, 8.3, 7.8, 2.9 Hz, 4H), 1.02 (d, J = 6.5 Hz, 6H), 0.86 (t, J =6.9 Hz, 3H). 425

518 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (s, 1H), 8.08 (d, 1H, J= 2.0 Hz), 7.86 (d, 1H, J = 5.2 Hz), 7.67 (d, 2H, J = 8.8 Hz), 6.99 (d,2H, J = 8.8 Hz), 6.92 (d, 1H, J = 2.0 Hz), 5.94 (d, 1H, J = 5.2 Hz),3.987 (t, 3H, J = 8.0 Hz), 3.68- 3.64 (m, 4H), 3.47-3.46 (m, 2H),3.45-3.43 (m, 5H), 3.29-3.27 (m, 2H), 3.26 (s, 3H), 2.93-2.91 (m, 4H),2.79-2.76 (m, 4H), 1.15 (t, 3H, J = 7.2 Hz). 426

524 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.03 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.61 (d, 2H, J = 8.4 Hz), 6.89 (d, 1H, J = 1.6Hz), 6.45 (d, 2H, J = 8.4 Hz), 5.95 (d, 2H, J = 5.6 Hz), 3.90-3.86 (m,4H), 3.72-3.68 (m, 2H), 3.68-3.65 (m, 1H), 3.54-3.51 (m, 2H), 3.42- 3.41(m, 4H), 3.30-3.24 (m, 4H), 2.65-2.60 (m, 2H), 2.52-2.50 (m, 1H),2.50-2.48 (m, 2H), 0.90-0.85 (m, 6H). 427

525 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 7.98 (s, 1H), 7.88 (d, 1H, J= 3.6 Hz), 7.73 (d, 1H, J = 8.4 Hz), 7.26 (t, 1H, J = 74.4 Hz), 6.95 (s,1H), 6.88 (d, 1H, J = 6.8 Hz), 6.73 (s, 1H), 5.96 (d, 1H, J = 4.4 Hzs),3.91-3.90 (m, 2H), 3.69-3.67 (m, 2H), 3.53-3.45 (m, 4H), 3.23-3.19 (m,4H), 2.55-2.51 (m, 4H), 2.36 (q, 2H, J = 7.2 Hz), 2.01-2.00 (m, 1H),1.03 (t, 3H, J = 7.2 Hz), 0.76-0.74 (m, 4H). 428

526 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.73 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.45-3.44 (m,4H), 3.39-3.37 (m, 4H), 3.35-3.36 (m, 3H), 3.15-3.04 (m, 6H), 2.58- 2.54(m, 1H), 2.17-2.10 (m, 2H), 1.90-1.86 (m, 2H), 1.82-1.77 (m, 2H),1.74-1.66 (m, 4H), 1.06 (t, 3H, J = 7.2 Hz). 429

526 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.06 (s, 1H), 7.86 (d, 1H, J= 5.2 Hz), 7.64 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.4 Hz), 6.93 (s,1H), 5.94 (d, 1H, J = 5.2 Hz), 3.75-3.70 (m, 2H), 3.69-3.65 (m, 2H),3.50-3.45 (m, 2H), 3.44- 3.40 (m, 2H), 3.15-3.13 (m, 4H), 2.73-2.67 (m,2H), 2.50-2.49 (m, 4H), 2.37 (q, 2H, J = 6.8 Hz), 2.05-2.02 (m, 2H),1.73-1.70 (m, 2H), 1.63-153 (m, 2H), 1.44-1.36 (m, 2H), 10.3 (t, 3H, J =6.8 Hz). 430

531 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.8 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.77- 7.64 (m, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.00(d, J = 1.9 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 4.75 (q, J = 9.1 Hz, 2H),3.65 (s, 4H), 3.58-3.39 (m, 4H), 2.88 (d, J = 10.9 Hz, 3H), 2.70 (p, J =6.7 Hz, 1H), 2.21 (t, J = 11.1 Hz, 2H), 1.76 (d, J = 12.4 Hz, 2H), 1.63(tt, J = 12.6, 6.3 Hz, 2H), 0.99 (d, J = 6.5 Hz, 6H). 431

531 1H-NMR (H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 1.6 Hz, 1H),7.84 (d, J = c5.3 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 8.0Hz, 2H), 6.69 (d, J = 1.3 Hz, 1H), 5.84 (d, J = 5.4 Hz, 1H), 3.87 (s,2H), 3.75 (s, 2H), 3.47 (d, J = 25.7 Hz, 5H), 3.15 (s, 2H), 2.54 (d, J =9.7 Hz, 5H), 2.08 (s, 1H), 1.91 (q, J = 20.9, 17.1 Hz, 3H), 1.81-1.72(m, 1H), 1.66 (bs, 6H), 1.58- 1.39 (m, 1H), 1.31 (s, 2H), 1.24 (d, J =3.8 Hz, 4H), 1.16 (s, 1H). 432

531 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.44 (d, 1H, J = 2.0 Hz),8.24 (d, 1H, J = 1.2 Hz), 7.91 (d, 1H, J = 5.6 Hz), 7.85 (d, 1H, J = 8.0Hz), 7.67 (dd, 1H, J = 8.4, 2.0 Hz), 7.16 (d, 1H, J = 2.0 Hz), 5.96 (d,1H, J = 5.6 Hz), 4.58 (d, 1H, J = 4.0 Hz), 3.76-3.72 (m, 2H), 3.68-3.64(m, 2H), 3.53-3.48 (m, 2H), 3.45-3.40 (m, 2H), 2.93-2.88 (m, 2H),2.76-2.69 (m, 1H), 2.57- 2.54 (m, 1H), 2.25-2.20 (m, 2H), 1.86-1.81 (m,2H), 1.80-1.72 (m, 2H), 1.70-1.60 (m, 5H), 1.44-1.34 (m, 2H), 1.25-1.14(m, 2H), 0.99 (d, 6H, J = 6.8 Hz). 433

536 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.43 (d, 1H, J = 2.4 Hz),8.43 (s, 1H), 8.03 (d, 1H, J = 1.2 Hz), 7.83 (d, 1H, J = 5.6 Hz), 7.62(d, 2H, J = 8.4 Hz), 7.61-7.58 (m, 1H), 7.36 (dd, 1H, J = 8.4, 5.2 Hz),6.93 (d, 2H, J = 8.4 Hz), 6.88 (d, 1H, J = 1.2 Hz), 5.90 (d, 1H, J = 5.6Hz), 3.69-3.67 (m, 4H), .42-3.30 (m, 8H), 3.16-3.13 (m, 4H), 2.37 (q,2H, J = 6.4 Hz), 1.42-1.40 (m, 2H), 1.31-1.28 (m, 2H), 1.04 (t, 3H, J =7.2 Hz). 434

539 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.2 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.76-3.72 (m,2H), 3.72-3.68 (m, 2H), 3.51-3.47 (m, 2H), 3.45-3.40 (m, 2H), 2.79- 2.75(m, 2H), 2.72-2.69 (m, 4H), 2.18-2.15 (m, 2H), 2.04-2.03 (m, 2H),1.82-1.81 (m, 1H), 1.75-1.72 (m, 3H), 1.61-1.57 (m, 3H), 1.43- 1.40 (m,3H), 0.99-0.97 (m, 6H). 435

539 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.2 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.77-3.72 (m,2H), 3.70-3.65 (m, 2H), 3.50-3.45 (m, 2H), 3.45-3.40 (m, 2H), 2.82- 2.79(m, 2H), 2.75-2.67 (m, 4H), 2.18-2.15 (m, 2H), 2.07-2.06 (m, 2H),1.84-1.83 (m, 1H), 1.80-1.75 (m, 3H), 1.60-1.54 (m, 3H), 1.46- 1.40 (m,3H), 0.99-0.96 (m, 6H). 436

540 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (s, 0.3H), 8.09 (d, 1H,J = 1.6 Hz), 7.87 (d, 1H, J = 5.6 Hz), 7.68 (d, 2H, J = 8.4 Hz), 7.00(d, 2H, J = 8.4 Hz), 6.94 (d, 1H, J = 1.2 Hz), 6.54 (s, 0.4H), 5.96 (d,1H, J = 5.6 Hz), 3.80-3.70 (m, 2H), 3.70-3.60 (m, 2H), 3.56-3.48 (m,2H), 3.45-3.38 (m, 2H), 3.35-3.20 (m, 8H), 2.80- 2.60 (m, 2H), 2.10-2.00(m, 2H), 1.78-1.68 (m, 2H), 1.66-1.50 (m, 2H), 1.48-1.34 (m, 2H),1.24-1.10 (m, 6H). 437

540 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.45 (s, 1H), 8.24 (s, 1H),7.91 (d, 1H, J = 6.0 Hz), 7.85 (d, 1H, J = 8.0 Hz), 7.68 (d, 1H, J = 8.0Hz), 7.16 (s, 1H), 5.97 (d, 1H, J = 5.6 Hz), 3.76- 3.73 (m, 2H),3.69-3.63 (m, 2H), 3.53-3.48 (m, 2H), 3.46-3.42 (m, 2H), 2.90-2.87 (m,2H), 2.74-2.68 (m, 3H), 2.57-2.49 (m, 1H), 2.24- 2.19 (m, 2H), 2.05-2.02(m, 2H), 1.78-1.70 (m, 4H), 1.70-1.57 (m, 4H), 1.45-1.39 (m, 2H), 0.98(d, 6H, J = 6.8 Hz). 438

541 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.04 (d, 1H, J = 1.6 Hz),7.83 (d, 1H, J = 5.6 Hz), 7.63 (d, 2H, J = 9.2 Hz), 7.35 (dd, 1H, J =4.8, 2.4 Hz), 6.93 (d, 2H, J = 8.4 Hz), 6.96-6.91 (m, 3H), 5.91 (d, 1H,J = 5.6 Hz), 3.73-3.55 (m, 4H), 3.41-3.18 (m, 8H), 3.15-3.13 (m, 4H),2.36 (q, 2H, J = 7.2 Hz), 1.46-1.43 (m, 2H), 1.21-1.18 (m, 2H), 1.03 (t,3H, J = 7.2 Hz). 439

541 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.04 (d, 1H, J = 2.0 Hz),7.84 (d, 1H, J = 5.6 Hz), 7.63 (d, 2H, J O 8.8 Hz), 7.50 (dd, 1H, J )5.2, 2.8 Hz), 7.23 (dd, 1H, J 2.8, 1.2 Hz), 6.94-6.90 (m, 4H), 5.91 (d,1H, J δ 5.6 Hz), 3.72-3.69 (m, 4H), 3.42-3.30 (m, 8H), 3.16-3.13 (m,4H), 2.37 (q, 2H, J 7.2 Hz), 1.35-1.32 (m, 2H), 1.17-1.15 (m, 2H), 1.03(t, 3H, J = 7.2 Hz). 440

542 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.04 (d, 1H, J = 1.6 Hz),7.84 (d, 1H, J = 5.2 Hz), 7.69 (d, 1H, J = 3.2 Hz), 7.64 (d, 2H, J = 8.8Hz), 7.61 (d, 1H, J = 3.2 Hz), 6.93 (d, 2H, J = 8 8Hz), 6.92 (d, 1H, J =1.6 Hz), 5.93 (d, 1H, J = 5.2 Hz), 3.80-3.60 (m, 4H), 3.50-3.36 (m, 4H),3.30-3.28 (m, 4H), 3.20-3.10 (m, 4H), 2.36 (q, 2H, J = 7.2 Hz),1.60-1.55 (m, 2H), 1.50- 1.40 (m, 2H), 1.03 (t, 3H, J = 7.2 Hz). 441

543 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.25 (br s, 1H), 8.04 (d, 1H,J = 1.6 Hz), 7.87 (d, 1H, J = 5.6 Hz), 7.62 (d, 2H, J = 8.4 Hz), 6.90(d, 1H, J = 1.6 Hz), 6.45 (d, 2H, J = 8.4 Hz), 5.95 (d, 2H, J = 5.6 Hz),3.88 (d, 4H), 3.75-3.71 (m, 2H), 3.69-3.64 (m, 2H), 3.52-3.48 (m, 2H),3.48-3.45 (m, 4H), 3.45-3.33 (m, 3H), 2.56- 2.52 (m, 1H), 2.50-2.41 (m,1H), 1.88-1.82 (m, 2H), 1.72-1.65 (m, 2H), 1.43-1.33 (m, 2H), 1.26-1.18(m, 2H), 0.87 (d, 6H, J = 6.4 Hz). 442

552 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.34 (s, 1H), 8.03 (d, 1H, J= 1.6 Hz), 7.87 (d, 1H, J = 5.6 Hz), 7.61 (d, 2H, J = 8.8 Hz), 6.90 (d,2H, J = 1.6 Hz), 6.44 (d, 1H, J = 8.8 Hz), 5.95 (d, 1H, J = 5.6 Hz),3.86 (s, 4H), 3.78-3.70 (m, 2H), 3.69-3.62 (m, 2H), 3.50-3.45 (m, 2H),3.44-3.38 (m, 2H), 3.25 (s, 4H), 2.76-2.66 (m, 2H), 2.26-2.20 (m, 1H),2.10-2.01 (m, 2H), 1.75-1.71 (m, 2H), 1.62-1.55 (m, 2H), 1.46- 1.40 (m,2H), 1.10-1.07 (m, 6H). 443

553 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.03 (d, 1H, J = 1.2 Hz),7.83 (d, 1H, J = 5.6 Hz), 7.62 (d, 2H, J = 8.8 Hz), 7.37 (dd, 1H, J =14.4, 8.0 Hz), 7.07-7.02 (m, 2H), 6.99-6.95 (m, 1H), 6.92 (d, 2H, J =8.8 Hz), 6.89 (d, 1H, J = 1.2 Hz), 5.90 (d, 1H, J = 5.2 Hz), 3.73-3.55(m, 4H), 3.41-3.18 (m, 8H), 3.14 (t, 4H, J = 4.4 Hz), 3.26 (q, 2H, J =7.2 Hz), 1.41-1.37 (m, 2H), 1.27-1.23 (m, 2H), 1.03 (t, 3H, J = 7.2 Hz).444

554 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (s, 1H), 8.15 (d, 1H, J= 1.6 Hz), 7.90 (d, 1H, J = 5.6 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.33 (d,2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.24 (d, 2H, J = 8.4 Hz),7.00 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.97-3.89 (m, 1H),3.85- 3.70 (m, 2H), 3.70-3.66 (m, 1H), 3.36-3.26 (m, 4H), 3.06-2.98 (m,1H), 2.79-2.71 (m, 2H), 2.,61-2.54 (m, 2H), 2.42-2.32 (m, 3H), 2.29-2.17 (m, 1H), 1.84-1.74 (m, 1H), 1.51-1.44 (m, 1H), 1.28-1.21 (m, 1H),1.08 (t, 3H, J = 7.2 Hz). 445

557 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.93 (d, J = 1.8 Hz, 1H),7.82 (d, J = 5.4 Hz, 1H), 7.68- 7.59 (m, 2H), 7.31-7.21 (m, 2H), 6.86(d, J Hz, 1= 1.8 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 3.86- 3.75 (m, 2H),3.65 (dd, J = 6.9, 3.5 Hz, 2H), 3.56-3.40 (m, 4H), 3.24-3.06 (m, 3H),2.80- 2.67 (m, 2H), 2.54 (dh, J = 14.0, 7.6 Hz, 4H), 2.14 (td, J = 11.8,2.9 Hz, 2H), 1.91-1.75 (m, 5H), 1.15 (t, J = 7.3 Hz, 3H). 446

565 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.8 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.76- 7.62 (m, 2H), 7.57 (dd, J = 7.6, 1.6 Hz, 2H),7.36 (t, J = 7.6 Hz, 2H), 7.25 (dd, J = 7.7, 5.4 Hz, 3H), 6.98 (d, J =1.9 Hz, 1H), 5.95 (d, J = 5.5 Hz, 1H), 5.63 (s, 1H), 3.77-3.63 (m, 2H),3.58 (d, J = 5.8 Hz, 2H), 3.44 (q, J = 5.4 Hz, 4H), 2.99 (dd, J = 17.5,9.4 Hz, 3H), 2.59 (ddt, J = 11.7, 9.7, 6.1 Hz, 4H), 2.34 (q, J = 7.1 Hz,2H), 2.02-1.87 (m, 2H), 1.81-1.55 (m, 4H), 1.02 (t, J = 7.1 Hz, 3H). 447

569 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.03 (d, 1H, J = 1.6 Hz),7.83 (d, 1H, J = 5.2 Hz), 7.62 (d, 2H, J = 8.8 Hz), 7.38-7.34 (m, 1H),7.28 (d, 1H, J = 8.4 Hz), 7.18 (s, 1H), 7.17 (d, 1H, J = 8.0 Hz), 6.92(d, 2H, J = 8.8 Hz), 6.89 (d, 1H, J = 1.6 Hz), 5.90 (d, 1H, J = 5.6 Hz),3.73-3.55 (m, 4H), 3.41-3.18 (m, 8H), 3.14 (t, 4H, J = 4.8 Hz), 2.36 (q,2H, J = 7.2 Hz), 1.41-1.37 (m, 2H), 1.27-1.24 (m, 2H), 1.03 (t, 3H, J =7.2 Hz). 448

479 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.68 (s, 1H), 8.31 (s, 1H),8.16 (d, 1H, J = 1.6 Hz), 7.91 (d, 1H, J = 5.6 Hz), 7.05 (d, 1H, J = 1.6Hz), 5.99 (d, 1H, J = 5.2 Hz), 4.08 (q, 2H, J = 7.2 Hz), 3.61-3.60 (m,4H), 3.56-3.54 (m, 4H), 3.47-3.46 (m, 4H), 2.73-2.67 (m, 1H), 2.57- 2.54(m, 4H), 1.22 (t, 3H, J = 7.2 Hz), 1.00 (d, 6H, J = 6.8 Hz). 449

402 450

417 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 9.07 (d, 1H, J = 2.0 Hz),8.38 (d, 1H, J = 1.2 Hz), 8.29 (dd, 1H, J = 8.4, 2.0 Hz), 7.94 (d, 2H, J= 5.6 Hz), 7.54 (d, 1H, J = 8.4 Hz), 7.21 (d, 1H, J = 1.2 Hz), 6.01 (d,1H, J = 5.6 Hz), 4.66-4.62 (m, 1H), 3.94-3.91 (m, 2H), 3.72-3.70 (m,2H), 3.57-3.54 (m, 2H), 3.53-3.49 (m, 2H), 3.30- 3.19 (m, 2H), 2.40-2.34(m, 1H), 1.99-1.85 (m, 4H), 0.79-0.75 (m, 4H). 451

417 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 9.06 (s, 1H), 8.36 (s, 1H),8.26 (dd, 1H, J1 = 8.4 Hz, J2 = 2.0 Hz), 7.94 (d, 1H, J = 5.6 Hz), 7.53(d, 1H, J = 8.4 Hz), 7.21 (s, 1H), 5.99 (d, 1H, J = 5.6 Hz), 4.62-4.58(m, 1H), 4.02-3.98 (m, 2H), 3.95-3.91 (m, 2H), 3.72-3.50 (m, 4H), 3.30-3.16 (m, 2H), 2.35-2.30 (m, 1H), 2.08-2.04 (m, 1H), 1.99-1.87 (m, 3H),0.79-0.73 (m, 4H). 452

417 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.2 Hz, 1H), 8.25(d, J = 1.8 Hz, 1H), 7.92 (d, J = 5.4 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H),7.75 (dd, J = 8.2, 2.3 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 5.97 (d, J =5.5 Hz, 1H), 4.06 (t, J = 7.6 Hz, 1H), 3.93 (s, 2H), 3.70 (s, 2H), 3.52(d, J = 32.7 Hz, 4H), 3.01 (ddd, J = 9.9, 7.6, 5.3 Hz, 1H), 2.89 (ddd, J= 9.9, 8.2, 6.6 Hz, 1H), 2.13 (dtd, J = 12.3, 7.7, 4.9 Hz, 1H), 2.02(tt, J = 7.7, 4.9 Hz, 1H), 1.85-1.69 (m, 2H), 1.58- 1.44 (m, 1H), 0.76(tt, J = 7.9, 2.9 Hz, 4H). 453

417 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.2 Hz, 1H), 8.21(d, J = 1.7 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H),7.71 (dd, J = 8.2, 2.3 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 5.94 (d, J =5.5 Hz, 1H), 4.01 (t, J = 7.6 Hz, 1H), 3.89 (s, 2H), 3.67 (s, 2H), 3.53(s, 2H), 3.45 (s, 2H), 2.98 (ddd, J = 9.9, 7.5, 5.4 Hz, 1H), 2.85 (ddd,J = 9.9, 8.2, 6.6 Hz, 1H), 2.09 (dtd, J = 12.1, 7.6, 4.8 Hz, 1H), 2.02-1.93 (m, 1H), 1.80-1.66 (m, 2H), 1.53-1.42 (m, 1H), 0.72 (tt, J = 7.9,2.9 Hz, 4H). 454

417 455

420 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.97 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.0 Hz,2H), 6.93 (d, J = 1.8 Hz, 1H), 5.99 (d, J = 5.4 Hz, 1H), 4.03 (s, 2H),3.85 (s, 2H), 3.63 (s, 2H), 3.51 (d, J = 25.3 Hz, 4H), 2.80 (s, 2H),2.60 (d, J = 9.9 Hz, 2H), 2.02 (tt, J = 7.8, 4.7 Hz, 1H), 1.51 (d, J =6.6 Hz, 3H), 0.92 (dt, J = 4.9, 3.8 Hz, 2H), 0.86 (ddt, J = 7.5, 4.6,2.6 Hz, 2H). 456

420 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 9.04 (s, 1H), 8.34 (s, 1H),8.25 (d, 1H, J = 8.0 Hz), 7.92 (s, 1H, J = 5.6 Hz), 7.52 (d, 1H, J = 8.0Hz), 7.17 (s, 1H), 6.65-6.62 (m, 1H), 6.00 (d, 1H, J = 5.6 Hz),4.56-4.54 (m, 1H), 3.53-3.51 (m, 4H), 3.45-3.44 (m, 4H), 3.25-3.22 (m,1H), 3.21-3.16 (m, 1H), 3.08 (quintet, 2H, J = 7.2 Hz), 2.32-2.30 (m,1H), 1.91-1.86 (m, 3H), 1.03 (t, 3H, J = 7.2 Hz). 457

420 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 9.05 (d, 1H, J = 8.4 Hz),8.36 (s, 1H), 8.26 (dd, 1H, J1 = 8.0 Hz, J2 = 2.0 Hz), 7.93 (d, 1H, J =5.2 Hz), 7.53 (d, 1H, J = 8.0 Hz), 7.17 (d, 1H, J = 1.2 Hz), 6.64 (t,1H, J = 5.2 Hz), 7.6.01 (d, 1H, J = 5.6 Hz), 4.58-4.54 (m, 1H),3.54-3.52 (m, 4H), 3.46-3.44 (m, 4H), 3.23-3.22 (m, 1H), 3.20-3.11 (m,1H), 3.09-3.06 (m, 2H), 2.34- 2.28 (m, 1H), 1.94-1.85 (m, 3H), 1.04 (t,3H, J = 7.2 Hz). 458

428 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.99 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.5 Hz, 1H), 7.80- 7.67 (m, 2H), 7.58-7.46 (m, 2H), 6.94(d, J = 1.8 Hz, 1H), 6.20 (tt, J = 3.5, 1.7 Hz, 1H), 5.98 (d, J = 5.5Hz, 1H), 4.01 (s, 2H), 3.93-3.75 (m, 4H), 3.61 (s, 3H), 3.53 (d, J = 5.3Hz, 3H), 3.48 (t, J = 6.1 Hz, 2H), 2.84 (tq, J = 5.8, 1.9 Hz, 2H), 2.01(tt, J = 7.8, 4.7 Hz, 1H), 0.99- 0.90 (m, 2H), 0.86 (ddt, J = 7.5, 4.6,2.5 Hz, 2H). 459

430 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.7 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.76- 7.66 (m, 2H), 7.54-7.42 (m, 2H), 7.01 (d, J =1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 3.91 (qd, J = 5.9, 2.8 Hz, 2H),3.70 (s, 2H), 3.50 (d, J = 29.4 Hz, 4H), 3.00 (ddd, J = 10.6, 8.3, 5.9Hz, 1H), 2.76 (ddd, J = 10.3, 8.5, 4.7 Hz, 1H), 2.06- 1.95 (m, 2H),1.82-1.69 (m, 2H), 1.58-1.46 (m, 1H), 1.35 (s, 3H), 0.75 (tt, J = 7.9,2.9 Hz, 4H). 460

430 461

431 1H-NMR (H NMR (400 MHz, MeOD) δ ppm 8.55-8.48 (m, 1H), 7.86 (d, 1H,J = 2.0 Hz), 7.82 (d, 1H, J = 5.6 Hz), 7.60 (d, 2H, J = 8.8 Hz), 6.82(d, 1H, J = 2.0 Hz), 6.70 (d, 2H, J = 8.8 Hz), 5.99 (d, 1H, J = 5.6 Hz),4.07-4.01 (m, 2H), 3.98- 3.95 (m, 1H), 3.89-3.83 (m, 2H), 3.65-3.58 (m,4H), 3.56-3.50 (m, 2H), 3.42-3.36 (m, 2H), 2.49-2.40 (m, 1H), 2.14-2.07(m, 1H), 2.05- 2.00 (m, 1H), 0.97-0.90 (m, 2H) ), 0.89-0.86 (m, 2H). 462

431 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 8.51 (s, 1H), 7.82 (d, 1H, J =1.6 Hz), 7.78 (d, 1H, J = 5.2 Hz), 7.57 (d, 2H, J = 8.8 Hz), 6.78 (d,1H, J = 1.2 Hz), 6.67 (d, 2H, J = 8.8 Hz), 5.94 (d, 1H, J = 5.6 Hz),3.98-3.95 (m, 3H), 3.82-3.80 (m, 2H), 3.60-3.54 (m, 4H), 3.48-3.46 (m,2H), 3.40-3.36 (m, 2H), 2.42-2.40 (m, 1HH), 2.13- 2.11 (m, 1H),2.00-1.98 (m, 1H), 0.90-0.88 (m, 2H), 0.84-0.80 (m, 2H). 463

  431.2 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.63 (dd, J = 2.1, 1.0 Hz,1H), 8.21 (d, J = 1.7 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.83-7.76 (m,2H), 7.13 (d, J = 1.8 Hz, 1H), 5.94 (d, J = 5.5 Hz, 1H), 3.90 (br.s,2H), 3.67 (br.s, 2H), 3.52 (br.s, 2H), 3.44 (br.s, 2H), 2.99 (dt, J =10.8, 7.1 Hz, 1H), 2.71 (ddd, J = 13.5, 9.2, 4.7 Hz, 1H), 1.98 (ddd, J =10.8, 8.2, 5.5 Hz, 2H), 1.75 (tt, J = 8.7, 6.2 Hz, 2H), 1.57-1.43 (m,1H), 1.35 (s, 3H), 0.72 (ddd, J = 10.9, 5.0, 2.4 Hz, 4H). 464

432 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.94 (d, J = 1.8 Hz, 1H),7.81 (d, J = 5.4 Hz, 1H), 7.73- 7.65 (m, 2H), 7.39 (d, J = 8.0 Hz, 2H),6.89 (d, J = 1.8 Hz, 1H), 5.92 (d, J = 5.4 Hz, 1H), 3.96 (d, J = 5.4 Hz,2H), 3.84 (ddt, J = 16.0, 8.6, 4.2 Hz, 5H), 3.68-3.53 (m, 3H), 3.53-3.38(m, 3H), 3.31 (p, J = 1.6 Hz, 1H), 3.11-2.91 (m, 2JH), 1.98 (ddd, J =9.3, 6.6, 4.0 Hz, 1H), 0.92 (ddd, J = 5.9, 4.7, 2.5 Hz, 2H), 0.85 (tdd,J = 7.4, 5.4, 1.9 Hz, 2H). 465

434 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.2 Hz, 1H), 8.20(d, J = 1.7 Hz, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H),7.70 (dd, J = 8.2, 2.3 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.27 (d, J =7.6 Hz, 1H), 5.95 (d, J = 5.5 Hz, 1H), 4.01 (t, J = 7.6 Hz, 1H), 3.75(dt, J = 13.5, 6.7 Hz, 1H), 3.48 (dd, J = 6.8, 3.2 Hz, 4H), 3.44-3.36(m, 4H), 2.97 (ddd, J = 9.9, 7.6, 5.3 Hz, 1H), 2.85 (ddd, J = 9.9, 8.2,6.7 Hz, 1H), 2.09 (dtd, J = 12.4, 7.7, 5.0 Hz, 1H), 1.81-1.64 (m, 2H),1.52-1.42 (m, 1H), 1.04 (d, J = 6.6 Hz, 6H). 466

434 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.2 Hz, 1H), 8.20(d, J = 1.7 Hz, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H),7.70 (dd, J = 8.2, 2.3 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.27 (d, J =7.6 Hz, 1H), 5.95 (d, J = 5.5 Hz, 1H), 4.01 (t, J = 7.6 Hz, 1H), 3.75(dt, J = 13.5, 6.7 Hz, 1H), 3.48 (dd, J = 6.8, 3.2 Hz, 4H), 3.44-3.36(m, 4H), 2.97 (ddd, J = 9.9, 7.6, 5.3 Hz, 1H), 2.85 (ddd, J = 9.9, 8.2,6.7 Hz, 1H), 2.09 (dtd, J = 12.4, 7.7, 5.0 Hz, 1H), 1.81-1.64 (m, 2H),1.52-1.42 (m, 1H), 1.04 (d, J = 6.6 Hz, 6H). 467

434 468

436 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.97 (dd, J = 5.9, 2.5 Hz,3H), 7.71-7.55 (m, 2H), 4.55 (dd, J = 10.8, 3.6 Hz, 1H), 4.21 (q, J =7.1 Hz, 2H), 4.18-4.09 (m, 2H), 4.09-3.91 (m, 2H), 3.82-3.69 (m, 4H),3.63-3.53 (m, 4H), 3.49- 3.37 (m, 2H), 3.30 (p, J = 1.7 Hz, 1H), 2.65(p, J = 1.9 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H). 469

437 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (s, 1H), 7.91 (d, 1H, J= 1.6 Hz), 7.85 (d, 1H, J = 5.6 Hz), 7.80 (s, 1H), 6.79 (d, 1H, J = 1.6Hz), 6.31 (d, 1H, J = 8.0 Hz), 5.97 (d, 1H, J = 5.2 Hz), 4.11-4.10 (m,1H), 3.81-3.76 (m, 1H), 3.51-3.50 (m, 4H), 3.41-3.39 (m, 4H), 3.21- 3.07(m, 1H), 2.95-2.90 (m, 1H), 2.75-2.70 (m, 1H), 2.46-2.43 (m, 2H),2.15-2.11 (m, 1H), 1.90-1.87 (m, 1H), 1.74-1.70 (m, 1H), 1.53- 1.50 (m,1H), 1.08 (d, 6H, J = 6.4 Hz). 470

437 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (s, 1H), 7.91 (s, 1H),7.85 (d, 1H, J = 5.6 Hz), 7.80 (s, 1H), 6.78 (s, 1H), 6.33 (d, 1H, J =8.0 Hz), 5.96 (d, 1H, J = 5.6 Hz), 4.14-4.08 (m, 1H), 3.80-3.74 (m, 1H),3.48-3.58 (m, 6H), 3.22-3.16 (m, 4H), 2.90-2.86 (m, 1H), 2.78- 2.74 (m,1H), 2.46-2.43 (m, 1H), 2.13-2.10 (m, 1H), 1.89-1.85 (m, 1H), 1.73-1.69(m, 1H), 1.52-1.48 (m, 1H), 1.08 (d, 6H, J = 6.8 Hz). 471

444 472

444 1H-NMR (H NMR (500 MHz, Methanol-d4) δ 8.02 (d, J = 1.8 Hz, 1H),7.87 (d, J = 5.4 Hz, 1H), 7.80- 7.70 (m, 2H), 7.56 (d, J = 8.0 Hz, 1H),6.98 (d, J = 2.0 Hz, 1H), 6.02 (d, J = 5.4 Hz, 1H), 4.91 (s, 2H), 4.04(s, 2H), 3.86 (s, 2H), 3.60 (d, J = 31.4 Hz, 5H), 3.22 (t, J = 7.4 Hz,6H), 2.22 (s, 1H), 2.03 (s, 1H), 1.44 (t, J = 7.3 Hz, 6H), 0.93 (d, J =4.1 Hz, 2H), 0.88 (d, J = 7.8 Hz, 1H). 473

446 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.6 Hz), 3.92-3.91 (m,2H), 3.80-3.60 (m, 2H), 3.60-3.55 (m, 2H), 3.50-3.46 (m, 4H), 3.35- 3.29(m, 1H), 2.54-2.53 (m, 1H), 2.02-1.99 (m, 1H), 1.37 (s, 6H), 0.84 (d,6H, J = 6.4 Hz), 0.76-0.72 (m, 4H). 474

428 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.87 (d, J = 5.4Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.06-6.98(m, 1H), 5.94 (d, J = 5.5 Hz, 1H), 3.88 (br.s, 2H), 3.66 (br.s, 2H),3.47 (vr.d, J = 27.3 Hz, 4H), 2.90-2.72 (m, 4H), 2.05-1.72 (m, 5H), 0.72(dd, J = 9.3, 6.3 Hz, 4H). 475

449 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.1 Hz, 1H), 8.21(d, J = 7.1 Hz, 1H), 7.89 (d, J = 5.4 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H),7.71 (dd, J = 8.2, 2.3 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 5.96 (d, J =5.5 Hz, 1H), 5.33-5.25 (m, 1H), 4.75 (t, J = 6.9 Hz, 2H), 4.49 (dd, J =7.5, 5.1 Hz, 2H), 4.02 (t, J = 7.6 Hz, 1H), 3.66 (br.s, 2H), 3.56 (br.s,2H), 3.50-3.41 (m, 4H), 2.98 (ddd, J = 9.9, 7.6, 5.4 Hz, 1H), 2.85 (ddd,J = 9.9, 8.2, 6.7 Hz, 1H), 2.10 (dtd, J = 12.4, 7.7, 5.0 Hz, 1H),1.81-1.64 (m, 2H), 1.54- 1.41 (m, 1H). 476

449 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.1 Hz, 1H), 8.21(d, J = 7.1 Hz, 1H), 7.89 (d, J = 5.4 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H),7.71 (dd, J = 8.2, 2.3 Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 5.96 (d, J =5.5 Hz, 1H), 5.33-5.25 (m, 1H), 4.75 (t, J = 6.9 Hz, 2H), 4.49 (dd, J =7.5, 5.1 Hz, 2H), 4.02 (t, J = 7.6 Hz, 1H), 3.66 (br.s, 2H), 3.56 (br.s,2H), 3.50-3.41 (m, 4H), 2.98 (ddd, J = 9.9, 7.6, 5.4 Hz, 1H), 2.85 (ddd,J = 9.9, 8.2, 6.7 Hz, 1H), 2.10 (dtd, J = 12.4, 7.7, 5.0 Hz, 1H),1.81-1.64 (m, 2H), 1.54- 1.41 (m, 1H).H-NMR ( 477

449 478

449 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.00 (d, J =1.8 Hz, 1H), 7.88-7.74 (m, 3H), 7.56-7.40 (m, 2H), 6.93 (d, J = 1.9 Hz,1H), 5.99 (d, J = 5.5 Hz, 1H), 4.37 (dd, J = 10.7, 3.5 Hz, 1H), 4.08(dd, J = 12.5, 3.3 Hz, 2H), 3.93 (p, J = 6.6 Hz, 1H), 3.90-3.77 (m, 2H),3.66-3.58 (m, 4H), 3.58-3.46 (m, 4H), 3.39-3.29 (m, 4H), 1.24-1.07 (m,6H). 479

452 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ 8.20 (d, 1H, J = 1.5 Hz), 7.91(d, 1H, J = 5.5 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.43 (d, 2H, J = 8.5 Hz),7.04 (d, 1H, J = 2.0 Hz), 5.99 (d, 1H, J = 6.0 Hz), 4.09 (q, 2H, J = 7.0Hz), 3.65-3.55 (m, 4H), 3.50-3.38 (m, 4H), 2.98-2.85 (m, 3H), 2.70-2.55(m, 1H), 2.45-2.35 (m, 1H), 2.23- 2.05 (m, 1H), 1.99-1.93 (m, 1H),1.80-1.70 (m, 1H), 1.60-1.50 (m, 1H), 1.22 (t, 3H, J = 7.0 Hz). 480

452 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 4.09 (q, 2H, J= 6.8 Hz), 3.65-3.50 (m, 4H), 3.50-3.38 (m, 4H), 2.98-2.80 (m, 3H),2.70-2.55 (m, 1H), 2.45-2.15 (m, 2H), 2.03- 1.95 (m, 1H), 1.85-1.70 (m,1H), 1.65-1.48 (m, 1H), 1.22 (t, 3H, J = 6.8 Hz). 481

455 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 1.7 Hz, 1H),7.98-7.84 (m, 3H), 7.57-7.44 (m, 2H), 7.07 (d, J = 1.9 Hz, 1H), 5.98 (d,J = 5.5 Hz, 1H), 3.92 (s, 2H), 3.71 (s, 2H), 3.51 (d, J = 25.6 Hz, 4H),3.27-3.07 (m, 3H), 2.90 (t, J = 12.8 Hz, 2H), 2.13 (d, J = 13.2 Hz, 2H),2.08-1.90 (m, 4H), 0.89-0.60 (m, 4H). 482

456 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 1.8 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.77- 7.67 (m, 2H), 7.34-7.24 (m, 2H), 7.01 (d, J =1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 3.92 (br.s, 2H), 3.69 (br.s, 2H),3.50 (br.d, J = 28,4 Hz, 4H), 2.94-2.78 (m, 6H), 2.02 (tt, J = 7.6, 4.9Hz, 1H), 1.74-1.59 (m, 6H), 0.75 (tt, J = 7.9, 2.9 Hz, 4H). 483

459 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.02 (d, J =1.8 Hz, 1H), 7.89-7.81 (m, 3H), 7.63-7.52 (m, 2H), 6.94 (d, J = 1.9 Hz,1H), 6.02 (d, J = 5.4 Hz, 1H), 5.49 (d, J = 5.3 Hz, 1H), 4.18 (q, J =7.1 Hz, 2H), 3.72 (d, J = 5.8 Hz, 4H), 3.59 (d, J = 13.5 Hz, 2H), 3.52(t, J = 5.1 Hz, 4H), 3.38 (dd, J = 13.1, 2.9 Hz, 2H), 2.44 (d, J = 14.5Hz, 2H), 2.39-2.23 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). 484

459 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.94 (s, 1H), 8.29 (s, 1H),8.18 (s, 1H), 8.17 (d, 1H, J = 8.0 Hz), 7.92 (d, 1H, J = 5.2 Hz), 7.54(d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 6.00 (d, 1H, J = 5.2 Hz), 4.02-3.98(m, 1H), 3.94-3.91 (m, 2H), 3.72-3.70 (m, 2H), 3.55-3.51 (m, 2H), 3.50-3.45 (m, 2H), 3.16-3.14 (m, 1H), 2.86-2.83 (m, 1H), 2.75-2.69 (m, 1H),2.23-2.18 (m, 1H), 2.04-2.01 (m, 1H), 1.85-1.79 (m, 2H), 1.72- 1.69 (m,1H), 0.99-0.97 (m, 6H), 0.78-0.74 (m, 4H). 485

459 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.48 (d, 1H, J = 1.6 Hz),8.26 (d, 1H, J = 1.2 Hz), 7.93 (d, 1H, J = 5.2 Hz), 7.86 (d, 1H, J = 8.4Hz), 7.72 (q, 1H, J1 = 8.4 Hz, J2 = 2.4 Hz), 7.14 (d, 1H, J = 1.6 Hz),5.98 (d, 1H, J = 5.2 Hz), 4.01- 3.92 (m, 2H), 3.73-3.70 (m, 2H),3.57-3.36 (m, 4H), 3.30-3.28 (m, 1H), 3.02-2.96 (m, 1H), 2.76-2.70 (m,2H), 2.50-2.48 (m, 1H), 2.44- 2.38 (m, 1H), 2.29-2.20 (m, 1H), 2.06-1.99(m, 1H), 1.81-1.74 (m, 1H), 1.08-1.04 (t, 6H, J = 6.8 Hz), 0.79-0.75 (m,4H). 486

459 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 8.51 (d, 1H, J = 2.0 Hz), 8.13(d, 1H, J = 1.6 Hz), 7.85 (d, 1H, J = 5.2 Hz), 7.65 (d, 1H, J = 2.4 Hz),7.60 (d, 1H, J = 8.0 Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.82 (d, 1H, J = 5.2Hz), 3.95-3.90 (m, 2H), 3.89-3.85 (m, 2H), 3.62-3.57 (m, 2H), 3.51-3.47(m, 2H), 3.48-3.42 (m, 1H), 3.35- 3.31 (m, 1H), 3.11-3.05 (m, 1H),2.93-2.85 (m, 1H), 2.71-2.65 (m, 2H), 2.45-2.38 (m, 1H), 2.01-1.89 (m,1H), 1.79-1.74 (m, 1H), 1.55- 1.45 (m, 1H), 1.22-1.19 (m, 6H), 0.84-0.78(m, 4H). 487

459 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.90 (d, 1H, J = 2.0 Hz),8.26 (d, 1H, J = 1.6 Hz), 8.13 (dd, 1H, J1 = 8.0 Hz, J2 = 2.0 Hz), 7.93(d, 1H, J = 5.2 Hz), 7.52 (d, 1H, J = 8.0 Hz), 7.13 (d, 1H, J = 1.2 Hz),6.00 (d, 1H, J = 5.6 Hz), 3.93- 3.92 (m, 2H), 3.85-3.81 (m, 1H),3.71-3.70 (m, 2H), 3.56-3.49 (m, 4H), 3.10-3.05 (m, 1H), 2.75-2.69 (m,1H), 2.62-2.59 (m, 1H), 2.20- 2.11 (m, 1H), 2.06-2.00 (m, 1H), 1.83-1.72(m, 2H), 1.68-1.61 (m, 1H), 0.94 (d, 6H, J = 6.4 Hz), 0.79-0.75 (m, 4H).488

460 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.00 (dd, J = 5.1, 1.8 Hz,1H), 7.86 (dd, J = 5.5, 3.8 Hz, 1H), 7.82-7.74 (m, 2H), 7.51-7.40 (m,2H), 6.96 (t, J = 2.4 Hz, 1H), 6.02 (d, J = 5.5 Hz, 1H), 4.06 (d, J =1.5 Hz, 2H), 3.86 (s, 2H), 3.64 (s, 2H), 3.56 (s, 2H), 3.27-3.11 (m,4H), 3.01 (d, J = 11.9 Hz, 3H), 2.27 (d, J = 14.3 Hz, 2H), 2.13-1.96 (m,1H), 0.99-0.81 (m, 3H). 489

460 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 9.03- 9.00 (m, 1H), 8.46-8.35(m, 1H), 8.25 (d, 1H, J = 1.6 Hz), 7.93 (d, 1H, J = 5.2 Hz), 7.91 (d,2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4 Hz), 7.09 (d, 1H, J = 1.6 Hz),6.00 (d, 1H, J = 5.2 Hz), 3.94-3.93 (m, 2H), 3.74-3.73 (m, 2H), 3.57-3.53 (m, 2H), 3.52-3.49 (m, 2H), 3.45-3.42 (m, 1H), 3.24-3.20 (m, 1H),3.18-3.14 (m, 1H), 3.00 (s, 3H), 2.95-2.92 (m, 1H), 2.23-2.22 (m, 1H),2.11-2.09 (m, 2H), 2.00-1.83 (m, 2H), 0.79-0.74 (m, 4H). 490

460 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.34 (s, 1H), 8.22 (d, 1H, J= 1.2 Hz), 7.92 (d, 1H, J = 5.6 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.42 (d,2H, J = 8.4 Hz), 7.08 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.2 Hz),3.93-3.92 (m, 2H), 3.72-3.71 (m, 2H), 3.58-3.53 (m, 2H), 3.51-3.45 (m,2H), 3.17-3.14 (m, 1H), 3.06-3.035 (m, 1H), 2.98 (s, 3H), 2.91-2.88 (m,1H), 2.70-2.69 (m, 1H), 2.17-2.16 (m, 1H), 2.05-2.01 (m, 2HH), 1.75-1.74 (m, 1H), 1.64-1.60 (m, 1H), 0.79-0.73 (m, 4H). 491

461 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 1.9 Hz, 1H),8.19 (t, J = 2.3 Hz, 1H), 7.92- 7.73 (m, 3H), 7.17 (t, J = 2.1 Hz, 1H),5.96 (dd, J = 5.6, 1.9 Hz, 1H), 4.03 (d, J = 24.3 Hz, 2H), 3.83 (s, 2H),3.62 (d, J = 6.6 Hz, 2H), 3.54-3.53 (m, 3H), 3.30 (p, J = 1.6 Hz, 2H),3.09 (tt, J = 12.4, 2.3 Hz, 2H), 3.01-2.89 (m, 2H), 2.17-2.05 (m, 2H),2.06-1.88 (m, 3H), 0.97-0.89 (m, 2H), 0.88 (d, J = 2.6 Hz, 2H). 492

461 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.91 (d, 1H, J= 5.5 Hz), 7.78 (d, 2H, J = 8.0 Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.00 (s,1H), 6.33 (d, 2H, J = 7.5 Hz), 5.99 (d, 1H, J = 5.5 Hz), 3.89-3.80 (m,1H), 3.79-3.65 (m, 8H), 3.45-3.41 (m, 1H), 3.29-3.19 (m, 2H), 3.13- 3.11(m, 2H), 2.51-2.15 (m, 2H), 1.80-1.79 (m, 2H), 1.23 (s, 3H), 1.08 (d,6H, J = 6.5 Hz). 493

462 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.98 (d, J = 1.8 Hz, 1H),7.85 (dd, J = 5.5, 2.3 Hz, 1H), 7.77-7.66 (m, 2H), 7.45-7.33 (m, 2H),6.94 (d, J = 1.9 Hz, 1H), 6.00 (dd, J = 5.6, 2.2 Hz, 1H), 5.49 (d, J =2.1 Hz, 1H), 4.04 (s, 2H), 3.85 (s, 2H), 3.63 (s, 2H), 3.54 (s, 2H),3.42 (s, 1H), 2.75 (s, 2H), 2.53 (s, 2H), 2.03 (tt, J = 7.9, 4.8 Hz,1H), 1.84 (d, J = 6.9 Hz, 5H), 1.49 (dd, J = 6.7, 2.2 Hz, 3H), 1.00-0.86(m, 2H), 0.86 (q, J = 2.8 Hz, 1H). 494

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.92 (d, 1H, J = 2.0 Hz),8.27 (s, 1H), 8.27 (s, 1H), 8.16 (dd, 2H, J = 8.4, 2.0 Hz), 7.91 (d, 1H,J = 5.6 Hz), 7.53 (d, 1H, J = 8.4 Hz), 7.11 (s, 1H), 6.62 (t, 1H, J =5.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 3.97-3.93 (m, 1H), 3.53-3.51 (m, 4H),3.45-3.44 (m, 4H), 3.16-3.12 (m, 1H), 3.07 (quintet, 2H, J = 6.8 Hz),2.84-2.77 (m, 1H), 2.71-2.65 (m, 1H), 2.24-2.15 (m, 1H), 1.86- 1.75 (m,2H), 1.72-1.65 (m, 1H), 1.03 (t, 3H, J = 6.8 Hz), 0.98-0.96 (m, 6H). 495

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.47 (d, 1H, J = 1.6 Hz),8.23 (d, 1H, J = 1.6 Hz), 7.90 (d, 1H, J = 5.6 Hz), 7.85 (d, 1H, J = 8.0Hz), 7.71 (d, 1H, J = 2.4 Hz), 7.69 (d, 1H, J = 2.0 Hz), 7.13 (d, 1H, J= 1.6 Hz), 6.61 (t, 1H, J = 5.2 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.52-3.51(m, 4H), 3.48-3.44 (m, 4H), 3.31-3.25 (m, 1H), 3.11-3.04 (m, 2H),2.98-2.94 (m, 1H), 2.74- 2.68 (m, 2H), 2.49-2.46 (m, 1H), 2.41-2.36 (m,1H), 2.27-2.18 (m, 1H), 1.77-1.70 (m, 1H), 1.06-1.01 (m, 9H). 496

462 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 8.51 (d, 1H, J = 1.6 Hz), 8.12(d, 1H, J = 1.6 Hz), 7.84 (d, 1H, J = 5.2 Hz), 7.64 (dd, 1H, J = 8.0,2.0 Hz), 7.58 (d, 1H, J = 8.0 Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.80 (d,1H, J = 5.6 Hz), 4.49 (t, 1H, J = 7.2 Hz), 3.64-3.60 (m, 4H), 3.54-3.50(m, 4H), 3.41-3.36 (m, 1H), 3.36-3.28 (m, 2H), 3.23-3.18 (m, 1H),2.97-2.94 (m, 1H), 2.77- 2.75 (m, 1H), 2.55-2.21 (m, 1H), 2.51-2.49 (m,1H), 2.41-2.36 (m, 1H), 1.91-1.88 (m, 1H), 1.18 (t, 3H, J = 7.2 Hz),1.16-1.12 (m, 6H). 497

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.90 (d, 1H, J = 1.6 Hz),8.25 (d, 1H, J = 1.6 Hz), 8.13 (dd, 1H, J1 = 8.4 Hz, J2 = 2.4 Hz), 7.92(d, 1H, J = 5.6 Hz), 7.52 (d, 1H, J = 8.4 Hz), 7.10 (d, 1H, J = 1.2 Hz),6.62 (t, 1H, J = 5.2 Hz), 6.00 (d, 1H, J = 5.2 Hz), 3.83 (m, 1H),3.54-3.52 (m, 4H), 3.45-3.43 (m, 4H), 3.12-3.05 (m, 3H), 2.75-2.69 (m,1H), 2.62-2.58 (m, 1H), 2.20- 2.11 (m, 1H), 1.83-1.78 (m, 2H), 1.68-1.61(m, 1H), 1.04 (t, 3H, J = 7.2 Hz), 0.94 (d, 6H, J = 6.0 Hz). 498

464 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.99 (d, J =1.8 Hz, 1H), 7.85 (d, J = 5.4 Hz, 1H), 7.82-7.73 (m, 2H), 7.53-7.37 (m,2H), 6.91 (d, J = 1.8 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 4.18 (q, J =7.1 Hz, 2H), 3.72 (t, J = 4.9 Hz, 4H), 3.50 (dd, J = 6.4, 3.8 Hz, 4H),3.43-3.24 (m, 6H), 2.35 (dd, J = 15.2, 2.6 Hz, 2H), 2.14 (ddd, J = 14.5,11.0, 6.5 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 499

465 500

470 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.45 (d, 1H, J = 2.0 Hz),8.26 (d, 1H, J = 1.0 Hz), 7.93 (d, 1H, J = 5.5 Hz), 7.86 (d, 1H, J = 8.0Hz), 7.67 (dd, 1H, J = 8.0, 2.5 Hz), 7.15 (d, 1H, J = 1.5 Hz), 5.98 (d,1H, J = 6.0 Hz), 3.74-3.3.69 (m, 2H), 3.69-3.62 (m, 1H), 3.60-3.53 (m,2H), 3.52-3.44 (m, 4H), 3.30-3.20 (m, 4H), 3.04- 2.92 (m, 2H), 2.70-2.56(m, 4H), 1.94-1.86 (m, 1H), 1.72-1.67 (m, 1H), 1.67-1.61 (m, 1H),1.56-1.44 (m, 1H). 501

472 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.01 (d, J =1.8 Hz, 1H), 7.87 (d, J = 5.5 Hz, 1H), 7.85-7.77 (m, 2H), 7.66-7.54 (m,2H), 6.97 (d, J = 1.9 Hz, 1H), 6.01 (d, J = 5.5 Hz, 1H), 4.08-3.94 (m,3H), 3.85 (s, 2H), 3.59 (d, J = 29.0 Hz, 4H), 3.54-3.36 (m, 3H), 2.53(d, J = 4.0 Hz, 2H), 2.03 (tt, J = 7.9, 4.7 Hz, 1H), 1.99-1.85 (m, 2H),1.77 (q, J = 10.4 Hz, 1H), 0.93 (dt, J = 5.3, 2.8 Hz, 2H), 0.87 (ddt, J= 7.6, 4.7, 2.4 Hz, 2H). 502

472 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.02 (d, J =1.8 Hz, 1H), 7.92-7.77 (m, 3H), 7.66-7.44 (m, 2H), 6.94 (d, J = 1.9 Hz,1H), 6.00 (d, J = 5.5 Hz, 1H), 3.93 (dt, J = 13.1, 6.6 Hz, 1H), 3.65(dd, J = 6.8, 3.5 Hz, 4H), 3.59-3.48 (m, 7H), 2.43 (d, J = 14.3 Hz, 2H),2.30 (td, J = 13.7, 3.9 Hz, 2H), 1.18 (d, J = 6.6 Hz, 6H). 503

472 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 7.90 (d, 1H, J= 6.0 Hz), 7.70-7.55 (m, 2H), 7.35 (d, 1H, J = 8.4 Hz), 7.01 (d, 1H, J =1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.00-3.80 (m, 2H), 3.80-3.60 (m, 2H),3.60-3.40 (m, 5H), 3.32-2.54 (m, 5H), 2.35 (s, 3H), 2.30-2.19 (m, 1H),2.06-1.94 (m, 1H), 1.85-1.65 (m, 1H), 1.21-0.95 (m, 6H), 0.83-0.65 (m,4H). 504

472 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.70- 7.55 (m, 2H), 7.35 (d, 1H, J = 8.8 Hz),7.01 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.00- 3.80 (m, 2H),3.80-3.60 (m, 2H), 3.60-3.40 (m, 5H), 3.32-2.54 (m, 5H), 2.35 (s, 3H),2.30-2.19 (m, 1H), 2.06-1.94 (m, 1HH), 1.85-1.70 (m, 1H), 1.21-0.95 (m,6H), 0.83-0.65 (m, 4H). 505

472 1H-NMR (H-NMR (400 MHz, MeOD) δ ppm 7.98 (d, 1H, J = 1.6 Hz), 7.86(d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.37 (d, 2H, J = 8.0 Hz),6.94 (d, 1H, J = 1.6 Hz), 6.01 (d, 1H, J = 5.2 Hz), 4.08-4.02 (m, 2H),3.89-3.81 (m, 2H), 3.79-3.38 (m, 2H), 3.67-3.52 (m, 6H), 3.31- 3.20 (m,2H), 2.64-2.56 (m, 1H), 2.08-2.00 (m, 1 506

472 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 7.88 (d, 1H, J= 5.2 Hz), 7.71 9d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.4 Hz), 7.01 9s,1H), 5.96 (s, 1H), 3.96-3.87 (m, 2H), 3.75-3.66 (m, 2H), 3.58-3.42 (m,4H), 3.31-3.20 (m, 2H), 3.18-3.10 (m, 1H), 3.06-2.96 (m, 1H), 2.92- 2.82(m, 1H), 2.08-1.92 (m, 2H), 1.82-1.76 (m, 1H), 1.08-1.02 (m, 6H), 0.95(d, 3H, J = 6.8 Hz), 0.79-0.72 (m, 4H). 507

472 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.4Hz), 7.02 (d, 1H, J = 5.2 Hz), 5.97 (d, 1H, J = 5.2 Hz), 3.92-3.91 (m,2H), 3.70-3.60 (m, 2H), 3.53-3.52 (m, 2H), 3.47-3.46 (m, 2H), 3.16- 3.15(m, 3H), 2.81-2.80 (m, 1H), 2.49-2.34 (m, 1H), 2.02-2.01 (m, 1H),1.46-1.45 (m, 1H), 1.22-1.21 (m, 1H), 1.12-1.11 (m, 6H), 0.96 (s, 3H),0.78-0.73 (m, 4H). 508

472 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (s, 1H), 7.90 (d, 1H, J= 5.2 Hz), 7.79-7.78 (m, 2H), 7.35-7.34 (m, 2H), 7.05-7.04 (m, 1H), 5.97(d, 1H, J = 5.6 Hz), 3.92-3.91 (m, 2H), 3.70-3.69 (m, 4H), 3.54-3.47 (m,6H), 2.02- 2.01 (m, 2H), 1.34-1.22 (m, 6H), 1.08-1.03 (m, 5H), 0.78-0.74(m, 4H). 509

472 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 1.7 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H),7.02 (d, J = 1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 3.99-3.85 (m, 2H),3.70 (s, 2H), 3.54 (s, 2H), 3.47 (s, 2H), 3.14-3.04 (m, 1H), 2.82-2.67(m, 2H), 2.06-1.96 (m, 1H), 1.77 (d, J = 4.7 Hz, 4H), 1.38 (s, 3H), 0.99(d, J = 6.3 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H), 0.79-0.70 (m, 4H). 510

472 511

473 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.21 (d, 1H, J = 1.2 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.83 (d, 2H, J = 8.0 Hz), 7.43 (d, 2H, J = 8.0Hz), 7.08 (d, 1H, J = 1.2 Hz), 6.00 (d, 1H, J = 5.6 Hz), 4.04-3.90 (m,2H), 3.80-3.60 (m, 2H), 3.60-3.40 (m, 5H), 3.05-2.85 (m, 3H), 2.70- 2.57(m, 1H), 2.15-1.65 (m, 5H), 1.60-1.50 (m, 1H), 1.50-1.40 (m, 1H),1.40-1.30 (m, 1H). 512

473 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.23 (s, 1H), 7.92 (d, 1H, J= 5.2 Hz), 7.86 (d, 2H, J = 8.0 Hz), 7.45 (d, 2H, J = 8.4 Hz), 7.10 (s,1H), 6.00 (d, 1H, J = 5.2 Hz), 4.10-3.87 (m, 2H), 3.80-3.65 (m, 2H),3.65-3.38 (m, 5H), 3.20- 2.60 (m, 5H), 2.35-1.70 (m, 4H), 1.70-1.55 (m,1H), 1.55-1.40 (m, 1H), 1.40-1.30 (m, 1H). 513

473 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.22 (d, 1H, J = 1.2 Hz),7.92 (d, 1H, J = 5.2 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4Hz), 7.09 (d, 1H, J = 1.2 Hz), 6.00 (d, 1H, J = 6.0 Hz), 4.04-3.90 (m,2H), 3.80-3.65 (m, 2H), 3.65-3.40 (m, 5H), 3.25-2.80 (m, 4H), 2.75- 2.60(m, 1H), 2.30-1.90 (m, 3H), 1.90-1.50 (m, 2H), 1.50-1.40 (m, 1H),1.40-1.30 (m, 1H). 514

473 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.22 (d, 1H, J = 1.2 Hz),7.92 (d, 1H, J = 5.2 Hz), 7.84 (d, 2H, J = 8.0 Hz), 7.44 (d, 2H, J = 8.4Hz), 7.09 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 4.04-3.90 (m,2H), 3.80-3.65 (m, 2H), 3.65-3.40 (m, 5H), 3.25-2.80 (m, 4H), 2.75- 2.60(m, 1H), 2.30-1.90 (m, 3H), 1.90-1.50 (m, 2H), 1.50-1.40 (m, 1H),1.40-1.30 (m, 1H). 515

473 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.97 (d, J = 1.9 Hz, 1H),7.85 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 7.9 Hz,2H), 6.94 (d, J = 1.9 Hz, 1H), 6.00 (d, J = 5.5 Hz, 1H), 5.42 (t, J =9.0 Hz, 1H), 4.04 (s, 2H), 3.85 (s, 2H), 3.75 (dt, J = 18.2, 8.7 Hz,2H), 3.66 (ddd, J = 11.0, 6.6, 4.2 Hz, 3H), 3.54 (s, 2H), 3.46 (ddd, J =8.9, 6.5, 4.4 Hz, 1H), 3.23 (td, J = 8.7, 6.6 Hz, 1H), 3.06 (t, J = 9.0Hz, 1H), 2.07-1.98 (m, 1H), 0.93 (dt, J = 5.3, 2.8 Hz, 2H), 0.87 (dt, J= 8.1, 2.9 Hz, 2H). 516

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.90 (d, 1H, J= 5.2 Hz), 7.76 (d, 2H, J = 7.6 Hz), 7.41 (d, 2H, J = 7.6 Hz), 7.04 (s,1H), 5.98 (d, 1H, J = 5.2 Hz), 3.94-3.92 (m, 2H), 3.71-3.69 (m, 3H),3.56-3.50 (m, 2H), 3.50- 3.44 (m, 2H), 2.98-2.94 (m, 1H), 2.78-2.72 (m,1H), 2.71-2.62 (m, 3H), 2.23-2.21 (m, 1H), 2.04-1.98 (m, 2H), 0.97 (d,6H, J = 6.0 Hz), 0.78-0.74 (m, 4H). 517

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 7.6 Hz), 7.42 (d, 2H, J = 7.6Hz), 7.05 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 3.94-3.92 (m,2H), 3.71-3.69 (m, 3H), 3.56-3.40 (m, 5H), 3.01-2.98 (m, 1H), 2.84- 2.64(m, 4H), 2.28-2.22 (m, 1H), 2.10-1.98 (m, 2H), 0.98 (d, 6H, J = 6.0 Hz),0.80-0.72 (m, 4H). 518

473 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 7.6 Hz), 7.42 (d, 2H, J = 7.6Hz), 7.05 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 3.94-3.92 (m,2H), 3.71-3.69 (m, 3H), 3.56-3.40 (m, 5H), 3.01-2.98 (m, 1H), 2.84- 2.64(m, 4H), 2.28-2.22 (m, 1H), 2.10-1.98 (m, 2H), 0.98 (d, 6H, J = 6.0 Hz),0.80-0.72 (m, 4H). 519

473 520

474 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.94 (d, J = 1.8 Hz, 1H),7.82 (d, J = 5.5 Hz, 1H), 7.73- 7.60 (m, 2H), 7.45-7.33 (m, 2H), 6.90(d, J = 1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.00 (s, 2H), 3.91 (d, J= 10.7 Hz, 1H), 3.82 (s, 2H), 3.70 (td, J = 11.3, 2.4 Hz, 1H), 3.66-3.56(m, 4H), 3.51 (s, 2H), 3.47-3.36 (m, 1H), 2.88 (p, J = 6.7 Hz, 1H),2.83-2.72 (m, 1H), 2.55 (td, J = 11.7, 3.3 Hz, 1H), 1.99 (tt, J = 7.9,4.8 Hz, 1H), 1.02 (d, J = 6.9 Hz, 3H), 0.90 (dt, J = 4.8, 2.8 Hz, 2H),0.84 (dd, J = 7.2, 2.6 Hz, 6H) 521

474 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.21 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.84 (d, 2H, J = 8.0 Hz), 8.47 (d, 2H, J = 8.0Hz), 7.07 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.95-3.90 (m,2H), 3.75-3.70 (m, 2H), 3.58-3.52 (m, 4H), 3.50-3.45 (m, 2H), 3.23- 3.21(m, 2H), 2.95 (s, 3H), 2.35-2.31 (m, 1H), 2.06-2.01 (m, 1H), 0.90 (d,6H, J = 8.4 Hz), 0.81-0.72 (m, 4H). 522

474 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 1.8 Hz, 1H), 7.90(d, J = 5.4 Hz, 1H), 7.82- 7.69 (m, 2H), 7.54-7.43 (m, 2H), 7.03 (d, J =1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 5.14 (s, 1H), 3.92 (s, 2H), 3.70(s, 2H), 3.50 (d, J = 29.4 Hz, 4H), 2.94-2.71 (m, 4H), 2.18-1.93 (m,3H), 1.04 (t, J = 6.4 Hz, 7H), 0.76 (tt, J = 7.9, 2.9 Hz, 4H). 523

474 524

474 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.97 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.5 Hz, 1H), 7.79- 7.66 (m, 2H), 7.50-7.41 (m, 2H), 6.93(d, J = 1.8 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 4.02 (s, 2H), 3.84 (s,2H), 3.62 (s, 2H), 3.53 (s, 2H), 3.20-3.04 (m, 4H), 3.04-2.89 (m, 2H),2.17- 2.04 (m, 2H), 2.04-1.85 (m, 3H), 1.14 (t, J = 7.0 Hz, 3H), 0.92(dt, J = 4.7, 2.8 Hz, 2H), 0.85 (ddt, J = 7.5, 4.6, 2.6 Hz, 2H). 525

474 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 9.18 (s, 2H), 8.36 (d, 1H, J= 1.6 Hz), 7.94 (d, 1H, J = 5.6 Hz), 7.24 (d, 1H, J = 1.6 Hz), 6.00 (d,1H, J = 5.6 Hz), 3.92-3.91 (m, 2H), 3.70-3.69 (m. 2H), 3.55-3.49 (m,2H), 3.32-3.21 (m, 2H), 2.88-2.85 (m, 2H), 2.76-2.70 (m, 2H), 2.26- 2.21(m, 2H), 2.03-2.02 (m, 1H), 1.94-1.92 (m, 2H), 1.78-1.75 (m, 2H), 0.98(d, 6H, J = 6.4 Hz), 0.77-0.74 (m, 4H). 526

475 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.72-8.64 (m, 1H), 8.26 (d, J =1.8 Hz, 1H), 7.92 (d, J = 5.4 Hz, 1H), 7.85 (dd, J = 5.6, 1.6 Hz, 2H),7.18 (d, J = 1.8 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 5.36 (s, 1H),3.96-3.89 (m, 2H), 3.70 (s, 2H), 3.52 (d, J = 31.6 Hz, 4H), 2.92 (d, J =9.8 Hz, 1H), 2.87-2.73 (m, 3H), 2.13 (dt, J = 12.9, 8.0 Hz, 1H), 2.03(dtd, J = 12.7, 7.8, 7.2, 4.8 Hz, 2H), 1.42-1.35 (m, 1H), 1.11 (d, J =15.0 Hz, 6H), 0.76 (tt, J = 7.9, 2.9 Hz, 4H). 527

475 528

475 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 2H), 8.18 (d, 1H, J= 1.6 Hz), 8.17 (s, 1H), 7.90 (d, 1H, J = 5.6 Hz), 7.06 (d, 1H, J = 1.6Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.93-3.90 (m, 2H), 3.78-3.72 (m, 4H),3.72-3.69 (m, 2H), 3.55-3.45 (m, 4H), 2.77-2.72 (m, 1H), 2.57- 2.50 (m,4H), 2.04-2.00 (m, 1H), 1.01 (d, 6H, J = 6.4 Hz), 0.79-0.74 (m, 4H). 529

475 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.68 (d, 1H, J = 0.8 Hz),8.31 (s, 1H), 8.17 (d, 1H, J = 1.6 Hz), 7.91 (d, 1H, J = 5.6 Hz), 7.08(d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.93-3.90 (m, 2H),3.71-3.70 (m, 2H), 3.56-3.54 (m, 6H), 3.33-3.31 (m, 2H), 2.73-2.67 (m,1H), 2.57- 2.54 (m, 4H), 2.05-1.99 (m, 1H), 1.00 (d, 6H, J = 6.4 Hz),0.78-0.74 (m, 4H). 530

475 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 0.8 Hz),7.89 (d, 1H, J = 4.8 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.29 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 6.63-6.60 (m, 1H), 5.98 (d, 1H, J = 5.6Hz), 3.54-3.50 (m, 4H), 3.43-3.40 (m, 4H), 3.29-3.25 (m, 1H), 3.04- 2.97(m, 3H), 2.75-2.69 (m, 2H), 2.47-2.39 (m, 2H), 2.24-2.20 (m, 1H),1.78-1.73 (m, 1H), 1.46-1.41 (m, 2H), 1.09-1.04 (m, 6H), 0.85 (t, 3H, J= 7.6 Hz). 531

475 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 6.0 Hz), 7.72 (d, 2H, J = 7.6 Hz), 7.29 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 6.31 (d, 1H, J = 7.6 Hz), 5.98 (d, 1H, J= 5.6 Hz), 3.81-3.76 (m, 1H), 3.53-3.51 (m, 4H), 3.44-3.43 (m, 4H),3.29-3.25 (m, 1H), 3.01-2.97 (m, 1H), 2.75- 2.68 (m, 2H), 2.47-2.37 (m,2H), 2.24-2.19 (m, 1H), 1.78-1.73 (m, 1H), 1.09-1.04 (m, 6H). 532

475 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 2.0 Hz), 6.63-6.60 (m, 1H), 5.98 (d, 1H, J = 5.6Hz), 3.53-3.52 (m, 4H), 3.44-3.43 (m, 4H), 3.29-3.25 (m, 1H), 3.04- 2.97(m, 3H), 2.73-2.69 (m, 2H), 2.47-2.39 (m, 2H), 2.23-2.20 (m, 1H),1.78-1.71 (m, 1H), 1.46-1.41 (m, 2H), 1.07-1.04 (m, 6H), 0.85 (t, 3H, J= 7.6 Hz). 533

475 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0Hz), 6.99 (d, 1H, J = 1.2 Hz), 6.31 (d, 1H, J = 7.6 Hz), 5.98 (d, 1H, J= 5.6 Hz), 3.81-3.76 (m, 1H), 3.52-3.51 (m, 4H), 3.44-3.43 (m, 4H),3.29-3.25 (m, 1H), 3.02-2.98 (m, 1H), 2.75- 2.69 (m, 2H), 2.47-2.37 (m,2H), 2.24-2.19 (m, 1H), 1.78-1.75 (m, 1H), 1.09-1.04 (m, 6H). 534

476 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.92 (d, J = 1.8 Hz, 1H),7.81 (d, J = 5.4 Hz, 1H), 7.72- 7.58 (m, 2H), 7.31-7.18 (m, 2H), 6.85(d, J = 1.8 Hz, 1H), 5.97 (d, J = 5.4 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H),3.70 (t, J = 5.0 Hz, 4H), 3.56- 3.37 (m, 4H), 3.03 (dt, J = 12.2, 3.1Hz, 2H), 2.77 (hept, J = 6.6 Hz, 1H), 2.53 (tt, J = 11.9, 4.1 Hz, 1H),2.34 (td, J = 11.8, 2.8 Hz, 2H), 1.95-1.84 (m, 2H), 1.83-1.69 (m, 2H),1.28 (t, J = 7.1 Hz, 3H), 1.12 (d, J = 6.6 Hz, 6H). 535

476 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J 1.8 Hz, 1H), 7.89 (d,J = 5.4 Hz, 1H), 7.73- 7.67 (m, 2H), 7.52-7.43 (m, 2H), 6.99 (d, J = 1.9Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.59 (s,4H), 3.49-3.40 (m, 4H), 3.09 (dd, J = 9.4, 4.2 Hz, 1H), 2.82-2.65 (m,2H), 1.78 (dd, J = 7.2, 4.4 Hz, 4H), 1.38 (s, 3H), 1.21 (t, J = 7.1 Hz,3H), 0.99 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H). 536

476 537

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.l35 (d, 2H, J =8.0 Hz), 7.04 (d, 1H, J = 1.6 Hz), 6.61 (t, 1H, J = 5.6 Hz), 5.99 (d,1H, J = 5.2 Hz), 3.77 (d, 1H, J = 8.4 Hz), 3.53-3.51 (m, 4H), 3.45-3.43(m, 4H), 3.12-3.06 (m, 2H), 3.02-2.98 (m, 1H), 2.85- 2.79 (m, 1H),2.74-2.66 (m, 3H), 2.25 (t, 1H, J = 11.2 Hz), 2.09 (t, 1H, J = 10.4 Hz),1.04 (t, 3H, J = 7.2 Hz), 0.98 (d, 6H, J = 6.4 Hz). 538

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.49 (s, 1H), 8.25 (s, 1H),7.92 (d, 1H, J = 5.6 Hz), 7.86 (d, 1H, J = 8.4 Hz), 7.71 (d, 1H, J = 8.4Hz), 7.14 (s, 1H), 6.61 (t, 1H, J = 5.2 Hz), 5.99 (d, 1H, J = 5.2 Hz),3.55-3.50 (m, 4H), 3.47-3.42 (m, 4H), 3.12-3.04 (m, 2H), 2.85-2.71 (m,4H), 2.25-2.17 (m, 2H), 1.85-1.81 (m, 1H), 1.75- 1.71 (m, 1H), 1.59-1.45(m, 2H), 1.04 (t, 3H, J = 7.2 Hz), 1.04-0.97 (m, 6H). 539

476 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.48 (d, 1H, J = 1.6 Hz),8.24 (d, 1H, J = 1.6 Hz), 7.92 (d, 1H, J = 5.2 Hz), 7.85 (d, 1H, J = 8.0Hz), 7.71-7.68 (m, 1H), 7.14 (d, 1H, J = 1.2 Hz), 6.60 (t, 1H, J = 5.2Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.53-3.51 (m, 4H), 3.45-3.44 (m, 4H),3.12-3.05 (m, 2H), 2.81-2.72 (m, 4H), 2.24- 2.14 (m, 2H), 1.84-1.81 (m,1H), 1.76-1.72 (m, 1H), 1.60-1.43 (m, 2H), 1.03 (t, 3H, J = 7.2 Hz),0.99-0.96 (m, 6H). 540

477 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.62 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.6 Hz), 6.31 (d, 1H, J = 7.6 Hz), 5.98 (d, 1H, J= 5.6 Hz), 5.79 (s, 1H), 3.82-3.66 (m, 1H), 3.60-3.47 (m, 6H), 3.46-3.38 (m, 4H), 3.24-3.18 (m, 2H), 2.44-2.34 (m, 1H), 1.07 (d, 6H, J = 6.8Hz), 0.90 (d, 6H, J = 6.0 Hz). 541

477 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.00 (d, J =1.8 Hz, 1H), 7.86 (d, J = 5.5 Hz, 1H), 7.82-7.69 (m, 2H), 7.54-7.36 (m,2H), 6.93 (d, J = 1.9 Hz, 1H), 6.00 (d, J = 5.5 Hz, 1H), 3.93 (p, J =6.6 Hz, 1H), 3.65 (dd, J = 6.6, 3.6 Hz, 4H), 3.54 (dd, J = 6.7, 3.5 Hz,4H), 3.42-3.34 (m, 4H), 3.04 (s, 3H), 2.38 (d, J = 14.5, 2H), 2.13 (dd,J = 26.5, 5.7 Hz, 1H), 1.23-1.12 (m, 7H). 542

477 1H-NMR (H NMR (400 MHz, 4d-MeOD) δ ppm 8.55 (m, 1H), 8.04 (dd, 1H, J= 7.6, 1.6 Hz), 7.91 (d, 1H, J = 5.2 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.52(d, 2H, J = 8.4 Hz), 6.95 (d, 1H, J = 2.0 Hz), 6.01 (d, 1H, J = 5.6 Hz),3.96-3.95 (m, 1H), 3.68-3.65 (m, 4H), 3.56-3.55 (m, 4H), 3.44- 3.42 (m,2H), 3.26-3.25 (m, 1H), 3.12 (s, 3H), 3.04-3.00 (m, 2H), 2.25-2.19 (m,3H), 1.21- 1.17 (m, 6H). 543

477 1H-NMR (H NMR (400 MHz, 6d-DMSO) δ ppm 8.32 (s, 1H), 8.19 (d, 1H, J= 2.0 Hz), 7.91 (d, 1H, J = 5.6 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.41 (d,2H, J = 8.4 Hz), 7.04 (d, 1H, J = 6.0 Hz), 6.32 (d, 1H, J = 7.6 Hz),6.00 (d, 1H, J = 5.6 Hz), 3.80- 3.75 (m, 1H), 3.55-3.50 (m, 4H),3.50-3.45 (m, 4H), 3.18-3.10 (m, 1H), 2.98 (s, 3H), 2.93-2.92 (m, 1H),2.82-2.80 (m, 1H), 2.70-2.66 (m, 1H), 2.19-2.18 (m, 1H), 2.03-1.98 (m,1H), 1.73- 1.687 (m, 1H), 1.60-1.55 (m, 1H), 1.09-1.06 (m, 6H). 544

477 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.48 (d, 1H, J = 2.0 Hz),8.24 (d, 1H, J = 2.0 Hz), 7.92 (d, 1H, J = 5.2 Hz), 7.85 (d, 1H, J = 8.4Hz), 7.71 (dd, 1H, J = 8.4, 2.4 Hz), 7.14 (d, 1H, J = 1.6 Hz), 5.99 (d,1H, J = 5.6 Hz), 4.09 (q, 2H, J = 7.2 Hz), 3.62-3.59 (m, 4H), 3.48-3.46(m, 4H), 2.82-2.72 (m, 4H), 2.25-2.14 (m, 2H), 1.84-1.80 (m, 1H),1.75-1.72 (m, 1H), 1.60- 1.45 (m, 2H), 1.22 (t, 3H, J = 7.2 Hz), 0.99-0.96 (m, 6H). 545

477 1H-NMR (H-NMR (500 MHz, CDCl3) δ ppm 8.53 (s, 1H), 8.14 (d, 1H, J =1.5 Hz), 7.87 (d, 1H, J = 5.0 Hz), 7.63-7.59 (m, 2H), 7.00 (d, 1H, J =1.5 Hz), 5.84 (d, 1H, J = 5.5 Hz), 4.21 (q, 2H, J = 7.2 Hz), 3.75-3.70(m, 4H), 3.52-3.49 (m, 1H), 3.50-3.45 (m, 4H), 3.33-3.20 (m, 3H),2.60-2.53 (m, 2H), 2.36-2.31 (m, 1H), 2.14- 2.10 (m, 1H), 2.01-1.95 (m,1H), 1.70-1.64 (m, 1H), 1.35-1.28 (m, 9H). 546

477 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 8.33 (d, 1H, J = 2.8 Hz), 8.06(d, 1H, J = 1.6 Hz), 7.83 (d, 1H, J = 5.6 Hz), 7.54 (d, 1H, J = 8.4 Hz),7.26-7.22 (m, 1H), 6.96 (d, 1H, J = 1.6 Hz), 5.80 (d, 1H, J = 5.6 Hz),4.52-4.48 (m, 1H), 3.65-3.59 (m, 4H), 3.55-3.50 (m, 4H), 3.34 (q, 2H, J= 7.2 Hz), 3.28-3.24 (m, 4H), 2.77-2.70 (m, 5H), 1.19 (t, 3H, J = 7.2Hz), 1.11 (d, 6H, J = 6.4 Hz). 547

477 1H-NMR (H-NMR (400 MHz, 4d-MeOD) δ ppm 9.08 (s, 2H), 8.14 (d, 1H, J= 1.2 Hz), 7.89 (d, 1H, J = 5.2 Hz), 7.06 (d, 1H, J = 0.8 Hz), 6.02 (d,1H, J = 5.6 Hz), 3.66-3.65 (m, 4H), 3.65-3.57 (m, 4H), 3.25 (q, 2H, J =7.2 Hz), 3.11-3.09 (m, 2H), 2.93-2.91 (m, 1H), 2.86-2.83 (m, 1H),2.48-2.43 (m, 2H), 2.07-2.01 (m, 4H), 1.17- 1.13 (m, 9H). 548

477 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.42 (d, 1H, J = 1.6 Hz),8.31 (s, 1H), 8.16 (d, 1H, J = 8.8 Hz), 7.96 (d, 1H, J = 6.0 Hz), 7.65(d, 1H, J = 8.8 Hz), 7.30 (d, 1H, J = 1.2 Hz), 6.66-6.61 (m, 1H), 6.02(d, 1H, J = 6.0 Hz), 3.56-3.51 (m, 4H), 3.50-3.45 (m, 4H), 3.10-3.05 (m,4H), 3.00-2.94 (m, 2H), 2.58-2.50 (m, 2H), 2.00- 1.90 (m, 4H), 1.10 (d,6H, J = 6.4 Hz), 1.04 (t, 3H, J = 7.2 Hz). 549

446 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.04 (t, J = 2.1 Hz, 1H),7.95-7.84 (m, 2H), 7.28-7.13 (m, 2H), 7.04 (d, J = 1.8 Hz, 1H), 5.96 (d,J = 5.5 Hz, 1H), 3.89 (br.s, 2H), 3.66 (br.s, 2H), 3.48 (br.d, J = 28.4Hz, 4H), 2.88 (s, 3H), 2.84- 2.72 (m, 4H), 1.98 (td, J = 7.7, 3.8 Hz,1H), 1.89 (d, J = 13.6 Hz, 2H), 1.76 (td, J = 13.5, 12.6, 4.8 Hz, 2H),0.79-0.65 (m, 4H). 550

478 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.15 (t, J = 1.8 Hz, 1H), 7.90(d, J = 5.4 Hz, 1H), 7.79- 7.68 (m, 2H), 7.54-7.41 (m, 2H), 7.00 (d, J =1.9 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 5.14 (s, 1H), 4.08 (q, J = 7.1Hz, 2H), 3.63-3.56 (m, 4H), 3.45 (t, J = 5.1 Hz, 4H), 2.90 (d, J = 9.7Hz, 1H), 2.85-2.70 (m, 3H), 2.10 (dt, J = 12.9, 8.0 Hz, 1H), 1.99 (dt, J= 12.5, 5.6 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 6.4 Hz, 6H).551

478 552

478 1H-NMR (H NMR (400 MHz, 4d-MeOD) δ ppm 9.11 (s, 2H), 8.18 (d, 1H, J= 1.6 Hz), 7.90 (d, 1H, J = 5.6 Hz), 7.07 (d, 1H, mJ = 2.0 Hz), 6.05 (d,1H, J = 5.2 Hz), 4.19 (q, 2H, J 7.2 Hz), 3.74-3.73 (m, 4H), 3.55-3.52(m, 4H), 3.28-3.27 (m, 2H), 3.14-3.06 (m, 2H), 2.76-2.75 (m, 2H), 2.22-2.10 (m, 4H), 1.31 (t, 3H, J = 7.2 Hz), 1.25 (d, 6H, J = 6.4 Hz). 553

478 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 2H), 8.17 (d, 1H, J= 1.6 Hz), 8.16 (s, 1H), 7.89 (d, 1H, J = 5.6 Hz), 7.03 (d, 1H, J = 1.6Hz), 6.61 (t, 1H, J = 5.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.78-3.72 (m,4H), 3.53-3.48 (m, 4H), 3.46-3.40 (m, 4H), 3.08 (q, 2H, J = 7.2 Hz),2.80-2.70 (m, 1H), 2.56-2.52 (m, 4H), 1.10- 1.00 (m, 9H). 554

478 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.68 (s, 1H), 8.31 (s, 1H),8.16 (d, 1H, J = 1.2 Hz), 7.90 (d, 1H, J = 5.2 Hz), 7.05 (d, 1H, J = 1.2Hz), 6.60 (t, 1H, J = 5.2 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.56-3.51 (m,8H), 3.45-3.43 (m, 4H), 3.11-3.05 (m, 2H), 2.73-2.67 (m, 1H), 2.57- 2.54(m, 4H), 1.05-1.00 (m, 9H). 555

479 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 2H), 8.19 (s, 1H),8.18 (d, 1H, J = 1.6 Hz), 7.90 (d, 1H, J = 5.6 Hz), 7.03 (d, 1H, J = 1.6Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.09 (q, 2H, J = 7.2 Hz), 3.80-3.73 (m,4H), 3.61-3.58 (m, 4H), 3.46-3.42 (m, 4H), 2.79-2.72 (m, 1H), 2.59- 2.55(m, 4H), 1.22 (t, 3H, J = 7.2 Hz), 1.02 (d, 6H, J = 6.4 Hz). 556

479 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.91 (d, 1H, J= 1.6 Hz), 7.85 (d, 1H, J = 5.6 Hz), 7.81 (s, 1H), 6.79 (d, 1H, J = 1.6Hz), 6.32 (d, 1H, J = 7.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 4.20-4.19 (m,1H), 3.81-3.76 (m, 1H), 3.51-3.50 (m, 4H), 3.41-3.39 (m, 4H), 3.07- 3.04(m, 1H), 2.80-2.74 (m, 2H), 2.41-2.35 (m, 1H), 2.20-2.17 (m, 1H),2.09-2.07 (m, 1H), 1.79-1.76 (m, 2H), 1.58-1.55 (m, 1H), 1.23- 1.09 (m,6H), 0.99-0.97 (m, 6H). 557

479 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.92 (d, 1H, J= 1.6 Hz), 7.86 (d, 1H, J = 5.6 Hz), 7.81 (s, 1H), 6.80 (d, 1H, J = 1.6Hz), 6.33 (d, 1H, J = 7.2 Hz), 5.97 (d, 1H, J = 5.2 Hz), 4.20-4.18 (m,1H), 3.81-3.75 (m, 1H), 3.52-3.50 (m, 4H), 3.41-3.39 (m, 4H), 3.06- 3.04(m, 1H), 2.81-2.74 (m, 2H),k 2.40-2.35 (m, 1H), 2.18 (t, 1H, J = 11.2Hz), 2.10-2.06 (m, 1H), 1.82-1.72 (m, 2H), 1.62-1.56 (m, 1H), 1.08 (d,6H, J = 6.8 Hz), 0.10-0.96 (m, 6H). 558

480 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δppm 8.22 (d, 1H, J 2.0 Hz), 7.92(d, 1H, J = 5.2 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4 Hz),7.05 (d, 1H, J = 1.2 Hz), 5.99 (d, 1H, J = 5.6 Hz), 5.34 (quintet, 1H, J= 5.6 Hz), 4.79 (t, 2H, J = 6.8 Hz), 4.53 (dd, 2H, J = 7.2, 1.2 Hz),3.72-3.68 (m, 2H), 3.64-3.60 (m, 2H), 3.55- 3.40 (m, 4H), 2.99-2.90 (m,3H), 2.70-2.55 (m, 1H), 2.25-2.15 (m, 1H), 2.10-1.98 (m, 1H), 1.92-1.66(m, 1H), 1.60-1.50 (m, 1H). 559

480 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.22 (d, 1H, J = 2.0 Hz),7.92 (d, 1H, J = 5.2 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.43 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.2 Hz), 5.99 (d, 1H, J = 5.6 Hz), 5.34 (quintet,1H, J = 5.6 Hz), 4.79 (t, 2H, J = 6.8 Hz), 4.53 (dd, 2H, J = 7.2, 1.2Hz), 3.72-3.68 (m, 2H), 2.64-2.60 (m, 2H), 3.55- 3.40 (m, 4H), 2.99-2.90(m, 3H), 2.70-2.55 (m, 1H), 2.25-2.15 (m, 1H), 2.10-1.98 (m, 1H),1.92-1.66 (m, 1H), 1.60-1.47 (m, 1H). 560

486 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 7.89 (d, 1H, J= 5.2 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.28-7.25 (m, 2H), 7.01 (s, 1H),5.97 (d, 1H, J = 5.2 Hz), 4.00-3.82 (m, 2H), 3.80- 3.60 (m, 2H),3.58-3.40 (m, 4H), 2.80-2.60 (m, 3H), 2.47-2.44 (m, 1H), 2.38-2.24 (m,1H), 2.20-1.96 (m, 2H), 1.86-1.76 (m, 1H), 1.75- 1.66 (m, 1H), 1.62-1.38(m, 3H), 1.32-1.16 (m, 1H), 0.90 (dd, 3H, J = 6.4, 2.8 Hz), 0.85 (t, 3H,J = 7.6 Hz), 0.80-0.70 (m, 4H). 561

486 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.15 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 4.00-3.82 (m,2H), 3.80-3.60 (m, 2H), 3.58-3.40 (m, 4H), 3.00-2.60 (m, 3H), 2.46- 2.40(m, 1H), 2.38-2.15 (m, 2H), 2.10-1.94 (m, 1H), 1.86-1.70 (m, 2H),1.66-1.40 (m, 3H), 1.36-1.24 (m, 1H), 1.00-0.90 (m, 3H), 0.86 (t, 3H, J= 7.2 Hz), 0.80-0.70 (m, 4H). 562

486 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.2 Hz), 4.00-3.82 (m,2H), 3.80-3.62 (m, 2H), 3.58-3.40 (m, 4H), 2.80-2.65 (m, 3H), 2.47- 2.40(m, 1H), 2.37-2.25 (m, 1H), 2.16-2.06 (m, 1H), 2.05-1.94 (m, 1H),1.86-1.76 (m, 1H), 1.75-1.66 (m, 1H), 1.60-1.32 (m, 3H), 1.30- 1.24 (m,1H), 0.90 (d, 3H, J = 6.8 Hz), 0.85 (t, 3H, J = 7.2 Hz), 0.80-0.70 (m,4H). 563

486 1H-NMR (H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.73 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.0Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 3.94-3.91 (m,2H), 3.71-3.70 (m, 2H), 3.54-3.46 (m, 4H), 2.84-2.81 (m, 2H), 2.46- 2.30(m, 2H), 2.22-2.19 (m, 1H), 2.03-2.01 (m, 1H), 1.75-1.20 (m, 7H),0.95-0.71 (m, 10H). 564

486 1H-NMR (H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0Hz), 7.02 (d, 1H, J = 1.2 Hz), 5.97 (d, 1H, J = 5.2 Hz), 3.94-3.91 (m,2H), 3.71-3.70 (m, 2H), 3.54-3.46 (m, 4H), 2.84-2.81 (m, 2H), 2.46- 2.30(m, 2H), 2.03-2.01 (m, 1H), 1.75-1.20 (m, 8H), 0.95-0.71 (m, 10H). 565

486 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 7.97 (d, 1H, J = 1.6 Hz),7.85 (d, 1H, J = 5.2 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.42 (d, 2H, J = 8.4Hz), 6.93 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 4.08-4.02 (m,2H), 3.90-3.84 (m, 2H), 3.68-3.62 (m, 2H), 3.58-3.54 (m, 2H), 2.88- 2.78(m, 3H), 2.70-2.60 (m, 2H), 2.36-2.25 (m, 2H), 2.08-2.00 (m, 1H),1.94-1.84 (m, 2H), 1.34-1.22 (m, 3H), 1.12 (d, 6H, J = 6.8 Hz),0.97-0.84 (m, 4H) 566

487 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.0Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.2 Hz), 3.94-3.92 (m,2H), 3.72-3.70 (m, 2H), 3.56-3.46 (m, 4H), 2.97-2.93 (m, 2H), 2.77- 2.73(m, 1H), 2.65-2.61 (m, 2H), 2.36-2.32 (m, 1H), 2.24-2.20 (m, 1H), 2.10(t, 1H, J = 10.4 Hz), 2.04-2.00 (m, 1H), 1.96 (s, 3H), 0.96 (d, 6H, J =6.8 Hz), 0.80-0.74 (m, 4H). 567

487 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.35 d, 2H, J = 8.0Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.2 Hz), 3.94-3.92 (m,2H), 3.72-3.70 (m, 2H), 3.56-3.46 (m, 4H), 2.97-2.94 (m, 1H), 2.90- 2.86(m, 1H), 2.77-2.73 (m, 1H), 2.65-2.61 (m, 2H), 2.36-2.32 (m, 1H),2.24-2.20 (m, 1H), 2.10 (t, 1H, J = 10.4 Hz), 2.04-2.00 (m, 1H), 1.96(s, 3H), 0.96 (d, 6H, J = 6.8 Hz), 0.80- 0.74 (m, 4H). 568

487 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.94-3.92 (m,2H), 3.72-3.70 (m, 2H), 3.50-3.45 (m, 2H), 3.37-3.32 (m, 2H), 2.97- 2.92(m, 1H), 2.91-2.86 (m, 1H), 2.77-2.71 (m, 1H), 2.65-2.61 (m, 2H),2.36-2.32 (m, 1H), 2.24-2.20 (m, 1H), 2.13-2.08 (m, 1H), 2.04- 2.00 (m,1H), 1.96 (s, 3H), 0.96 (d, 6H, J = 6.8 Hz), 0.80-0.74 (m, 4H). 569

487 1H-NMR (H NMR (400 MHz, CDCl3) δ ppm 7.92 (d, 1H, J = 1.6 Hz), 7.83(d, 1H, J = 5.2 Hz), 7.63 (d, 2H, J = 8.4 Hz), 7.54 (d, 2H, J = 8.4 Hz),6.71 (d, 1H, J = 1.6 Hz), 5.82 (d, 1H, J = 5.2 Hz), 3.94-3.90 (m, 2H),3.90-3.85 (m, 2H), 3.57-3.51 (m, 2H), 3.48-3.43 (m, 2H), 3.21- 3.15 (m,1H), 2.95-2.87 (m, 1H), 2.85-2.77 (m, 1H), 2.74 (heptet, 1H, J = 6.4Hz), 2.55-2.45 (m, 2H), 2.45-2.38 (m, 1H), 1.79-1.74 (m, 1H), 1.39 (s,3H), 1.10-1.07 (m, 3H), 1.06-1.01 (m, 5H), 0.84-0.79 (m, 2H). 570

487 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 2.0 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.50 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 2.0 Hz), 5.97 (d, 1H, J = 5.6 Hz), 3.96-3.90 (m,2H), 3.73-3.69 (m, 2H), 3.59-3.54 (m, 2H), 3.53-3.47 (m, 2H), 3.10- 3.05(m, 1H), 2.72-2.67 (m, 1H), 2.64-2.56 (m, 2H), 2.41-2.37 (m, 1H),2.33-2.28 (m, 2H), 2.26-2.22 (m, 1H), 2.06-1.99 (m, 1H), 1.21 (s, 3H),1.00-0.95 (m, 6H), 0.78-0.74 (m, 4H). 571

488 572

488 573

488 574

488 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.98 (d, J =1.8 Hz, 1H), 7.86 (d, J = 5.4 Hz, 1H), 7.81-7.63 (m, 2H), 7.41-7.24 (m,2H), 6.90 (d, J = 1.9 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 4.87 (s, 2H),4.26 (p, J = 7.8 Hz, 1H), 3.94-3.83 (m, 2H), 3.63-3.52 (m, 3H), 3.33 (p,J = 1.7 Hz, 4H), 3.21 (td, J = 12.6, 3.0 Hz, 2H), 3.00-2.84 (m, 0H),2.67 (s, 2H), 2.23- 2.12 (m, 2H), 2.12-1.97 (m, 2H), 1.42 (d, J = 6.6Hz, 6H). 575

488 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 8.78 (d, 1H, J = 2.0 Hz), 8.14(d, 1H, J = 1.2 Hz), 7.98- 7.92 (m, 1H), 7.85 (d, 1H, J = 6.4 Hz), 7.64(d, 1H, J = 8.4 Hz), 7.05 (d, 1H, mJ = 1.6 Hz), 5.82 (d, 1H, J = 5.2Hz), 3.97-3.92 (m, 2H), 3.90- 3.95 (m, 2H), 3.62-3.57 (m, 2H), 3.52-3.46(m, 2H), 3.30-3.24 (m, 1H), 3.01-2.93 (m, 1H), 2.81-2.75 (m, 2H),2.65-2.56 (m, 1H), 2.52- 2.45 (m, 3H), 1.80-1.75 (m, 1H), 1.46 (s, 3H),1.48 (s, 3H), 1.11-1.01 (m, 8H), 0.85-0.79 (m, 2H). 576

488 1H-NMR (H-NMR (500 MHz, CDCl3) δ ppm 8.81 (s, 1H, J = 1.5 Hz), 8.15(d, 1H, J = 2.0 Hz), 7.99 (d, 1H, J = 7.5 Hz), 7.87 (d, 1H, J = 5.0 Hz),7.66 (d, 1H, J = 8.5 Hz), 7.07 (s, 1H), 5.83 (d, 1H, J = 5.0 Hz),3.98-3.91 (m, 2H), 3.90-3.86 (m, 2H), 3.76-3.80 (m, 1H), 3.68-3.60 (m,2H), 3.52-3.46 (m, 2H), 3.28-3.25 (m, 1H), 3.08- 3.02 (m, 1H), 2.90-2.80(m, 2H), 2.70-2.62 (m, 2H), 2.62-2.55 (m, 1H), 1.81-1.77 (m, 1H),2.24-2.21 (m, 1H), 1.54 (s, 3H), 1.14-1.08 (m, 6H), 1.06-1.04 (m, 2H),0.90-0.82 (m, 2H). 577

489 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.88 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4Hz), 6.98 (d, 1H, J = 1.6 Hz), 6.31 (d, 1H, J = 7.6 Hz), 5.97 (d, 1H, J= 5.6 Hz), 3.85-3.70 (m, 1H), 3.60-3.48 (m, 4H), 3.46-3.38 (m, 4H),2.84-2.75 (m, 2H), 2.73-2.60 (m, 2H), 2.22- 2.08 (m, 2H), 1.86-1.77 (m,1H), 1.76-1.68 (m, 1H), 1.60-1.50 (m, 1H), 1.50-1.38 (m, 1H), 1.07 (d,6H, J = 6.4 Hz), 1.00-0.90 (m, 6H). 578

489 1H-NMR (H-NMR (500 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.5 Hz),7.89 (d, 1H, J = 5.0 Hz), 7.72 (d, 2H, J = 8.5 Hz), 7.27 (*d, 2H, J =8.5 Hz), 6.99 (s, 1H), 6.31 (d, 2H, J = 7.5 Hz), 5.98 (d, 1H, J = 5.5Hz), 3.79-3.78 (m, 1H), 3.52-3.51 (m, 4H), 3.44-3.43 (m, 4H), 2.81-2.79(m, 2H), 2.74-2.70 (m, 2H), 2.19-2.14 (m, 2H), 1.83- 1.81 (m, 1H),1.74-1.71 (m, 1H), 1.56-1.54 (m, 1H), 1.46-1.44 (m, 1H), 1.09-1.08 (m,6H), 0.98-0.96 (m, 6H). 579

489 1H-NMR (H-NMR (500 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 7.89 (d, 1H, J= 5.2 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0 Hz), 6.99 (s,1H), 6.63-6.60 (m, 1H), 5.98 (d, 1H, J = 5.6 Hz), 3.54-3.51 (m, 4H),3.44-3.43 (m, 4H), 3.03- 2.99 (m, 2H), 2.81-2.79 (m, 2H), 2.73-2.67 (m,2H), 2.19-2.14 (m, 2H), 1.84-1.81 (m, 1H), 1.75-1.74 (m, 1H), 1.56-1.41(m, 4H), 0.98- 0.96 (m, 6H), 0.85 (t, 3H, J = 7.6 Hz). 580

489 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.13 (d, 1H, J = 1.2 Hz),7.88 (d, 1H, J = 5.2 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.0Hz), 6.98 (d, 1H, J = 1.2 Hz), 6.61 (t, 1H, J = 5.6 Hz), 5.97 (d, 1H, J= 5.6 Hz), 3.60-3.38 (m, 8H), 3.05-2.95 (m, 2H), 2.85-2.60 (m, 4H),2.22-2.05 (m, 2H), 1.86-1.68 (m, 2H), 1.60- 1.34 (m, 4H), 1.00-0.90 (m,6H), 0.84 (t, 3H, J = 7.2 Hz). 581

489 582

489 583

490 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 1.8 Hz, 1H), 7.86(d, J = 5.4 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H),7.03 (d, J = 1.9 Hz, 1H), 5.93 (d, J = 5.5 Hz, 1H), 3.88 (br.s, 2H),3.66 br.(s, 2H), 3.47 (br.d, J = 27.5 Hz, 4H), 2.70 (d, J = 11.3 Hz,3H), 2.13- 1.80 (m, 5H), 0.98 (d, J = 6.5 Hz, 6H), 0.80- 0.64 (m, 4H).584

490 1H-NMR (H NMR (500 MHz, Methanol-d4) δ 8.01 (t, J = 2.2 Hz, 1H),7.87 (d, J = 5.4 Hz, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.13 (dd, J = 8.0,1.7 Hz, 1H), 7.07 (dd, J = 12.9, 1.7 Hz, 1H), 6.98 (d, J = 1.8 Hz), 1H),6.01 (d, J = 5.4 Hz, 1H), 4.04 (s, 2H), 3.86 (s, 2H), 3.65 (s, 2H), 3.55(s, 2H), 3.09 (d, J = 11.5 Hz, 2H), 2.85 (s, 1H), 2.62 (t, J = 12.4 Hz,1H), 2.42 (s, 2H), 2.03 (tt, J = 8.2, 4.7 Hz, 1H), 1.93 (d, J = 13.0 Hz,2H), 1.86-1.72 (m, 2H), 1.15 (d, J = 6.6 Hz, 7H), 0.93 (dt, J = 5.6, 3.0Hz, 2H), 0.87 (dt, J = 8.0, 1.3 Hz, 2H). 585

490 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.34 (s, 1H), 7.15 (d, 1H, J= 1.5 Hz), 7.90 (d, 1H, J = 5.5 Hz), 7.74 (d, 2H, J = 8.5 Hz), 7.37 (d,2H, J = 8.5 Hz), 6.99 (d, 1H, J = 2.0 Hz), 5.98 (d, 1H, J = 5.5 Hz),4.09 (q, 2H, J = 7.0 Hz), 3.70- 3.41 (m, 8H), 2.68-2.65 (m, 1H),2.56-2.54 (m, 2H), 2.49-2.45 (m, 2H), 2.05-2.03 (m, 2H), 1.74-1.71 (m,2H), 1,22 (t, 3H, J = 7.0 Hz), 1.18 (s, 3H), 0.95 (d, 6H, J = 6.5 Hz).586

490 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.26 (s, 1H), 8.14 (d, 1H, J= 1.5 Hz), 7.89 (d, 1H, J = 5.0 Hz), 7.70 9d, 2H, J = 8.0 Hz), 7.28 (d,2H, J = 8.0 Hz), 6.91 (d, 1H, J = 1.5 Hz), 5.95 (d, 1H, J = 5.5 Hz),4.29-4.24 (m, 1H), 4.11-4.08 (m, 2H), 3.90-3.86 (m, 3H), 3.41-3.40 (m,1H), 3.23-3.20 (m, 1H), 3.05-3.04 (m, 1H), 2.85- 2.83 (m, 2H), 2.80-2.73(m, 2H), 2.50-2.20 (m, 2H), 1.75-1.74 (m, 1H), 1.73-1.72 (m, 1H),1.54-1.53 (m, m1H), 1.52-1.51 (m, 1H), 1.29 (d, 3H, J = 6.5 Hz), 1.22(t, 3H, J = 7.0 Hz), 1.01- 0.99 (m, 6H). 587

490 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.76 (d, 2H, J = 1.6 Hz), 6.62 (t, 1H, J = 5.6Hz), 5.99 (d, 1H, J = 5.2 Hz), 3.53-3.51 (m, 4H), 3.45-3.43 (m, 4H),3.12-3.06 (m, 2H), 2.98-2.94 (m, 1H), 2.90-2.88 (m, 1H), 2.77- 2.75 (m,1H), 2.66-2.60 (m, 2H), 2.36 (t, 1H, J = 10.8 Hz), 2.22 (t, 1H, J = 9.2Hz), 2.11 (t, 1H, J = 10.4 Hz), 1.96 (s, 3HH), 1.03 (t, 3H, J = 7.6 Hz),0.98 (d, 6H, J = 6.0 Hz). 588

490 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.47 (d, 1H, J = 2.0 Hz),8.24 (d, 1H, J = 2.0 Hz), 7.91 (d, 1H, J = 5.2 Hz), 7.85 (d, 1H, J = 7.6Hz), 7.69 (dd, 1H, J = 8.0, 2.0 Hz), 7.13 (d, 1H, J = 1.6 Hz), 6.31 (d,1H, J = 7.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.84-3.74 (m, 1H), 3.53-3.52(m, 4H), 3.46-3.44 (m, 4H), 2.82-2.72 (m, 4H), 2.25-2.14 (m, 2H),1.84-1.72 (m, 2H), 1.60- 1.45 (m, 2H), 1.08 (d, 6H, J = 6.8 Hz), 0.99-0.96 (m, 6H). 589

490 1H-NMR (H-NMR (500 MHz, CDCl3) δ ppm 8.52 (s, 1H), 8.13 (d, 1H, J =1.5 Hz), 7.86 (d, 1H, J = 5.5 Hz), 7.61-7.57 (m, 2H), 7.02 (d, 1H, J =1.5 Hz), 5.81 (d, 1H, J = 5.0 Hz), 4.31 (d, 1H, J = 7.0 Hz), 4.05-3.98(m, 1H), 3.64-3.60 (m, 4H), 3.58-3.52 (m, 4H), 3.33-3.29 (m, 1H),3.25-3.10 (m, 2H), 2.48-2.42 (m, 2H), 2.10- 2.04 (m, 2H), 2.00-1.91 (m,2H), 1.60-1.54 (m, 1H), 1.30-1.20 (m, 6H), 1.20 (d, 6H, J = 6.5 Hz). 590

491 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.8 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H),7.00 (d, J = 1.9 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 4.56-4.42 (m, 2H),3.63-3.51 (m, 4H), 3.44 (t, J = 4.9 Hz, 4H), 3.17 (s, 3H), 1.83 (s, 3H),1.08 (s, 9H). 591

491 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.16 (s, 1H), 7.90 (d, 1H, J= 5.2 Hz), 7.75 9d, 2H, J = 8.0 Hz), 7.56 (d, 2H, J = 8.4 Hz), 7.01 (d,1H, J = 1.2 Hz), 6.63-6.59 (m, 1H), 5.99 (d, 1H, J = 5.6 Hz), 4.56-4.43(s, 1H), 3.55-3.38 (m, 8H), 3.15-3.00 (m, 2H), 2.90-2.52 (m, 3H), 2.49-2.20 (m, 2H), 1.91-1.70 (m, 2H), 1.70-1.40 (m, 2H), 1.10-0.85 (m, 9H).592

491 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.17 (s, 1H), 7.90 (d, 1H, J= 5.2 Hz), 7.89-7.70 (m, 2H), 7.57 (d, 2H, J = 8.4 Hz), 7.02 (s, 1H),6.63-6.59 (m, 1H), 5.99 (d, 1H, J = 5.2 Hz), 4.63-4.38 (s, 1H),3.55-3.38 (m, 8H), 3.15-3.00 (m, 2H), 2.90-2.52 (m, 3H), 2.49-2.20 (m,2H), 2.00-1.40 (m, 4H), 1.40-0.75 (m, 9H). 593

491 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.19 (s, 1H), 7.92 (d, 1H, J= 5.6 Hz), 7.83 (d, 2H, J = 8.0 Hz), 8.46 (d, 2H, J = 8.0 Hz), 7.04 (s,1H), 6.32 (d, 1H, J = 7.6 Hz), 5.99 (d, 1H, J = 5.2 Hz), 3.82-3.76 (m,1H), 3.55-3.50 (m, 6H), 3.48-3.43 (m, 4H), 3.22-3.18 (m, 2H), 2.95 (s,3H), 2.36-2.31 (m, 1H), 1.09 (d, 6H, J = 6.4 Hz), 0.90 (d, 6H, J = 6.0Hz). 594

491 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.94 (d, J = 1.8 Hz, 1H),7.87-7.77 (m, 1H), 7.75-7.64 (m, 2H), 7.48-7.35 (m, 2H), 6.88 (d, J =1.7 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 4.02-3.82 (m, 2H), 3.77-3.59 (m,7H), 3.55-3.38 (m, 6H), 2.91 (p, J = 6.7 Hz, 1H), 2.80 (dt, J = 11.7,2.0 Hz, 1H), 2.58 (td, J = 11.7, 3.3 Hz, 1H), 1.17 (d, J = 6.6 Hz, 6H),1.04 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H). 595

491 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 1.7 Hz, 1H), 7.85(d, J = 5.4 Hz, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H),6.96 (d, J = 1.8 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H), 5.94 (d, J = 5.5 Hz,1H), 5.12 (s, 1H), 3.74 (h, J = 6.7 Hz, 1H), 3.48 (dd, J = 6.8, 3.3 Hz,4H), 3.38 (dd, J = 6.8, 3.4 Hz, 4H), 2.94-2.66 (m, 4H), 2.11-2.03 (m,1H), 2.01-1.90 (m, 1H), 1.06-0.97 (m, 12H). 596

491 597

491 1H-NMR (H NMR (400 MHz, CDCl3) δ ppm 7.91 (d, 1H, J = 1.2 Hz), 7.83(d, 1H, J = 5.2 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.54 (d, 2H, J = 8.4 Hz),6.68 (d, 1H, J = 1.2 Hz), 5.82 (d, 1H, J = 5.2 Hz), 4.19 (q, 2H, J = 7.2Hz), 3.72-3.69 (m, 4H), 3.45-3.41 (m, 4H), 3.14-3.10 (m, 1H), 2.92-2.85(m, 1H), 2.83-2.74 (m, 1H), 2.72 (heptet, 1H, J = 6.4 Hz), 2.53-2.46 (m,2H), 2.45-2.38 (m, 1H), 1.39 (s, 3H), 1.29 (t, 3H, J = 7.2 Hz), 1.08 (d,3H, J = 6.4 Hz), 1.03 (d, 3H, J = 6.4 Hz). 598

491 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (s, 1H), 7.90 (d, 1H, J= 5.6 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.50 (d, 2H, J = 8.0 Hz), 7.00 (s,1H), 5.97 (d, 1H, J = 5.6 Hz), 4.90 (q, 2H, J = 7.2 Hz), 3.62-3.60 (m,4H), 3.47-3.45 (m, 4H), 3.12-3.04 (m, 1H), 2.72-2.66 (m, 1H), 2.64- 2.56(m, 2H), 2.41-2.37 (m, 1H), 2.33-2.22 (m, 3H), 1.24-1.20 (m, 6H),1.00-0.95 (m, 6H). 599

492 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.98 (d, J = 1.8 Hz, 1H),7.85 (d, J = 5.4 Hz, 1H), 7.78- 7.70 (m, 2H), 7.48-7.40 (m, 2H), 6.91(d, J = 1.8 Hz, 1H), 6.01 (d, J = 5.5 Hz, 1H), 5.41 (tt, J = 6.2, 5.1Hz, 1H), 4.90 (ddd, J = 7.3, 6.2, 1.0 Hz, 2H), 4.65 (ddd, J = 7.6, 5.1,0.9 Hz, 2H), 3.75 (d, J = 35.1 Hz, 5H), 3.53 (dd, J = 6.6, 3.9 Hz, 4H),3.19-3.05 (m, 2H), 3.00 (s, 3H), 2.99-2.90 (m, 2H), 2.18-2.05 (m, 2H),1.96 (ddd, J = 13.8, 12.2, 4.4 Hz, 2H). 600

492 1H-NMR (H NMR (500 MHz, 4d-MeOD) δ ppm 8.57 (s, 1H), 8.03 (d, 1H, J= 2.0 Hz), 7.88 (d, 1H, J = 5.5 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.50 (d,2H, J = 8.5 Hz), 6.95 (d, 1H, J = 1.5 Hz), 6.04 (d, 1H, J = 5.5 Hz),5.43 (quintet, 1H, J = 5.5 Hz), 4.93 (t, 2H, J = 7.0 Hz), 4.67 (dd, 2H,J = 8.0, 5.5 Hz), 3.83-3.82 (m, 2H), 3.73-3.72 (m, 2H), 3.56-3.54 (m,4H), 3.47-3.46 (m, 1H), 3.44- 3.43 (m, 1H), 3.11 (s, 3H), 3.08-3.06 (m,1H), 2.99-2.98 (m, 1H), 2.41-2.40 (m, 1H), 2.20- 2.19 (m, 1H), 2.16-2.12(m, 1H), 1.94-1.93 (m, 1H). 601

492 1H-NMR (H NMR (500 MHz, 4d-MeOD) δ ppm 8.57 (s, 1H), 8.03 (d, 1H, J= 2.0 Hz), 7.88 (d, 1H, J = 5.5 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.50 (d,2H, J = 8.5 Hz), 6.95 (d, 1H, J = 1.5 Hz), 6.04 (d, 1H, J = 5.5 Hz),5.43 (quintet, 1H, J = 5.5 Hz), 4.93 (t, 2H, J = 7.0 Hz), 4.67 (dd, 2H,J = 8.0, 5.5 Hz), 3.83-3.82 (m, 2H), 3.73-3.72 (m, 2H), 3.56-3.54 (m,4H), 3.47-3.46 (m, 1H), 3.44- 3.43 (m, 1H), 3.11 (s, 3H), 3.08-3.06 (m,1H), 2.99-2.98 (m, 1H), 2.41-2.40 (m, 1H), 2.20- 2.19 (m, 1H), 2.16-2.12(m, 1H), 1.94-1.93 (m, 1H). 602

492 603

492 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 1.8 Hz, 1H), 7.86(d, J = 5.4 Hz, 1H), 7.77- 7.71 (m, 2H), 7.38-7.31 (m, 2H), 6.98 (d, J =1.8 Hz, 1H), 5.94 (d, J = 5.5 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H),3.58-3.51 (m, 4H), 3.45- 3.38 (m, 4H), 2.95-2.86 (m, 5H), 2.76-2.63 (m,2H), 2.39 (p, J = 6.3 Hz, 1H), 2.16 (ddd, J = 12.3, 7.2, 4.7 Hz, 1H),2.04 (dt, J = 13.1, 7.7 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H), 0.99 (d, J =6.2 Hz, 6H). 604

492 605

492 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.76 (s, 1H), 8.25 (s, 1H),7.95-7.91 (m, 2H), 7.88-7.85 (m, 1H), 7.15 (s, 1H), 6.61-6.59 (m, 1H),5.98 (d, 1H, J = 5.6 Hz), 4.76 (s, 1H), 3.53-3.52 (m, 4H), 3.45-3.44 (m,4H), 3.11-3.05 (m, 2H), 2.81-2.75 (m, 1H), 2.69-2.66 (m, 1H), 2.59- 2.56(m, 1H), 2.46-2.37 (m, 2H), 1.90-1.84 (m, 1H), 1.77-1.74 (m, 1H),1.61-1.57 (m, 1H), 1.45-1.42 (m, 1H), 1.03 (t, 3H, J = 7.2 Hz), 1.0-0.97(m, 6H). 606

492 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, 1H, J = 1.6 Hz),8.28-8.25 (m, 1H), 7.94-7.90 (m, 2H), 7.87-7.85 (m, 1H), 7.15 (d, 1H, J= 1.2 Hz), 6.61-6.59 (m, 1H), 5.98 (d, 1H, J = 5.6 Hz), 4.76 (s, 1H),3.53-3.52 (m, 4H), 3.45- 3.44 (m, 4H), 3.11-3.05 (m, 2H), 2.81-2.74 (m,1H), 2.68-2.66 (m, 1H), 2.58-2.56 (m, 1H), 2.46-2.36 (m, 2H), 1.90-1.84(m, 1H), 1.79- 1.74 (m, 1H), 1.60-1.57 (m, 1H), 1.45-1.43 (m, 1H), 1.03(t, 3H, J = 7.6 Hz), 1.0-0.97 (m, 6H). 607

492 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.1 Hz, 1H), 8.24(d, J = 1.7 Hz, 1H), 7.91 (d, J = 5.4 Hz, 1H), 7.90-7.80 (m, 2H), 7.14(d, J = 1.8 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H),5.36 (s, 1H), 3.78 (h, J = 6.7 Hz, 1H), 3.57-3.48 (m, 4H), 3.48-3.40 (m,4H), 2.93 (d, J = 9.7 Hz, 1H), 2.88-2.72 (m, 3H), 2.14 (dt, J = 15.1,7.9 Hz, 1H), 2.09- 1.98 (m, 1H), 1.10-1.00 (m, 12H). 608

492 609

493 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.54 (dd, J = 2.2, 1.1 Hz,1H), 8.20 (d, J = 1.9 Hz, 1H), 7.94-7.78 (m, 3H), 7.24-7.06 (m, 1H),6.01 (d, J = 5.5 Hz, 1H), 5.41 (tt, J = 6.3, 5.1 HzZ, 1H), 4.90 (ddd, J= 7.3, 6.3, 1.0 Hz, 2H), 4.66 (ddd, J = 7.5, 5.1, 0.9 Hz, 2H), 3.89-3.64(m, 5H), 3.55 (dd, J = 6.5, 3.8 Hz, 4H), 3.30 (p, J = 1.6 Hz, 4H),3.17-3.06 (m, 2H), 3.01-2.93 (m, 1H), 2.14 (dd, J = 14.5, 2.4 Hz, 2H),2.04- 1.89 (m, 2H). 610

494 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 2.0 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 2.0 Hz), 5.99 (d, 1H, J = 5.6 Hz), 4.09 (q, 2H, J= 6.8 Hz), 3.65-3.55 (m, 4H), 3.55-3.40 (m, 4H), 2.82-2.72 (m, 3H),2.70-2.60 (m, 1H), 2.40-2.25 (m, 1H), 2.05- 1.90 (m, 2H), 1.80-1.70 (m,1H), 1.60-1.50 (m, 1H), 1.22 (t, 3H, J = 6.8 Hz), 1.05-0.92 (m, 6H). 611

494 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 2.0 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 2.0 Hz), 5.99 (d, 1H, J = 5.6 Hz), 4.09 (q, 2H, J= 6.8 Hz), 3.65-3.55 (m, 4H), 3.55-3.40 (m, 4H), 2.82-2.72 (m, 3H),2.70-2.60 (m, 1H), 2.40-2.25 (m, 1H), 2.05- 1.90 (m, 2H), 1.80-1.70 (m,1H), 1.60-1.50 (m, 1H), 1.22 (t, 3H, J = 6.8 Hz), 1.05-0.92 (m, 6H). 612

494 1H-NMR (H NMR (500 MHz, Methanol-d4) δ 8.00 (t, J = 2.2 Hz, 12H),7.86 (d, J = 5.4 Hz, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.12 (dd, J = 8.0,1.7 Hz, 1H), 7.06 (dd, J = 12.9, 1.7 Hz, 1H), 6.94 (d, J = 1.8 Hz, 1H),6.01 (d, J = 5.5 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.72 (d, J = 5.9 Hz,4H), 3.51 (dd, J = 6.3, 3.9 Hz, 4H), 3.08 (d, J = 11.5 Hz, 2H),2.91-2.77 (m, 1H), 2.61 (dd, J = 13.9, 10.0 Hz, 1H), 2.42 (t, J = 1.8Hz, 2H), 1.91 (t, J = 17.0 Hz, 2H), 1.86-1.67 (m, 2H), 1.30 (t, J = 7.1Hz, 2H), 1.14 (t, J = 6.6 Hz, 7H). 613

495 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.72 (s, 1H), 8.31 (s, 1H),7.97-7.91 (m, 3H), 7.20 (s, 1H), 6.02-6.0 (m, 1H), 4.11-4.08 (m, 2H),3.66- 3.58 (m, 4H), 3.52-3.49 (m, 4H), 2.85-2.80 (m, 2H), 2.70-2.65 (m,2H), 2.43-2.35 (m, 1H), 2.13-1.99 (m, 1H), 1.97-1.89 (m, 1H), 1.85- 1.75(m, 1H), 1.60-1.51 (m, 1H), 1.23 (t, 3H, J = 7.0 Hz), 1.02-0.99 (m, 6H).614

495 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.73 (s, 1H), 8.31 (s, 1H),7.96-7.90 (m, 3H), 7.20 (s, 1H), 6.0 (d, 1H, J = 5.6 Hz), 4.08 (q, 2H, J= 7.2 Hz), 3.66-3.59 (m, 4H), 3.53-3.46 (m, 4H), 2.85-2.80 (m, 2H),2.70-2.65 (m, 2H), 2.43- 2.31 (m, 1H), 2.07-1.93 (m, 2H), 1.85-1.71 (m,1H), 1.61-1.50 (m, 1H), 1.23 (t, 3H, J = 7.2 Hz), 1.01-0.98 (m, 6H). 615

497 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.99 (d, J = 1.8 Hz, 1H),7.85 (t, J = 5.2 Hz, 1H), 7.83- 7.74 (m, 2H), 7.59-7.48 (m, 2H), 6.94(d, J = 1.9 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 4.04 (s, 2H), 3.86 (s,2H), 3.65 (s, 2H), 3.55 9s, 2H), 3.07 (d, J = 12.2 Hz, 2H), 2.86 (p, J =6.6 Hz, 1H), 2.75-2.62 (m, 2H), 2.26-2.07 (m, 4H), 2.00 (tt, J = 7.9,4.7 Hz, 1H), 1.16 (d, J = 6.6 Hz, 6H), 0.94 (dt, J = 4.9, 3.0 Hz, 2H),0.92- 0.81 (m, 2H). 616

499 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.2 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.64 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 5.80 (s, 1H),3.76-3.69 (m, 2H), 3.65-3.62 (m, 1H), 3.60-3.50 (m, 4H), 3.49-3.40 (m,4H), 3.32-3.27 (m, 1H), 3.26-3.20 (m, 2H), 2.70- 2.58 (m, 2H), 2.48-2.30(m, 3H), 0.92 (d, 6H, J = 6.0 Hz). 617

500 1H-NMR (H-NMR (500 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 7.08-7.05 (m, 1H), 7.00 (d, 1H, J = 1.2 Hz), 5.98 (d, 1H, J = 5.2Hz), 3.55-3.51 (m, 4H), 3.45-3.43 (m, 4H), 3.30-3.27 (m, 2H), 2.82- 2.80(m, 2H), 2.74-2.65 (m, 4H), 2.18-2.16 (m, 2H), 1.84-1.81 (m, 1H),1.75-1.74 (m, 1H), 1.46-1.41 (m, 2H), 0.99-0.97 (m, 6H). 618

500 1H-NMR (H-NMR (500 MHz, DMSO-d6) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 7.07-7.04 (m, 1H), 7.00 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2Hz), 3.55-3.54 (m, 4H), 3.46-3.45 (m, 4H), 3.30-3.27 (m, 2H), 2.81- 2.79(m, 2H), 2.74-2.65 (m, 4H), 2.19-2.14 (m, 2H), 1.83-1.80 (m, 1H),1.75-1.71 (m, 1H), 1.56-1.45 (m, 2H), 0.99-0.96 (m, 6H). 619

501 1H-NMR (H NMR (500 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.92 (d, 1H, J= 5.5 Hz), 7.75 (d, 2H, J = 7.0 Hz), 7.58 (d, 2H, J = 7.0 Hz), 7.03 (s,1H), 5.99 (d, 1H, J = 5.0 Hz), 3.94-3.93 (m, 2H), 3.72-3.71 (m, 2H),3.56-3.52 (m, 2H), 3.48- 3.43 (m, 2H), 2.65-2.64 (m, 1H), 2.63-2.60 (m,3H), 2.39-2.37 (m, 2H), 2.07-2.03 (m, 2H), 1.92 (s, 3H), 1.39 (s, 3H),0.94-0.91 (m, 6H), 0.79-0.76 (m, 4H). 620

501 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.95 (d, 1H, J = 1.6 Hz), 7.85(d, 1H, J = 6.4 Hz), 7.68- 7.60 (m, 4H), 6.73 (d, 1H, J = 2.0 Hz), 5.85(d, 1H, J = 5.2 Hz), 4.00-3.95 (m, 2H), 3.93-3.87 (m, 2), 3.60-3.55 (m,2H), 3.55-3.50 (m, 2H), 3.52-3.48 (m, 2H), 2.81-2.71 (m, 2H), 2.70- 2.60(m, 1H), 2.47-2.45 (m, 1H), 2.25-2.22 (m, 1H), 2.02 (s, 3H), 1.48 (s,3H), 1.16-1.14 (m, 1H), 1.07-1.04 (m, 2H), 1.01-0.94 (m, 6H), 0.85-0.82(m, 2H). 621

502 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.7 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H),6.98 (d, J = 1.8 Hz, 1H), 5.97 (d, J = 5.4 Hz, 1H), 4.87 (p, J = 7.4 Hz,1H), 3.59 (s, 4H), 3.44 (t, J = 5.1 Hz, 4H), 2.89 (d, J = 10.8 Hz, 3H),2.69 (d, J = 21.9 Hz, 1H), 2.26 (dtd, J = 12.2, 8.6, 7.7, 3.6 Hz, 4H),2.01 (ddt, J = 16.1, 10.9, 5.4 Hz, 2H), 1.76 (d, J = 13.2 Hz, 3H),1.70-1.50 (m, 2H), 0.99 (d, J = 6.5 Hz, 7H). 622

503 623

503 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.04 (d, 1H, J = 1.2 Hz),7.87 (d, 1H, J = 5.6 Hz), 7.62 (d, 2H, J = 8.4 Hz), 6.91 (d, 1H, J = 1.6Hz), 6.45 (d, 2H, J = 8.4 Hz), 5.97 (d, 1H, J = 5.2 Hz), 4.93-4.75 (s,1H), 3.94-3.92 (m, 2H), 3.85 (s, 4H), 3.70-3.66 (m, 2H), 3.54-3.42 (m,4H), 3.21 (m, 4H), 2.70-2.60 (m, 1H), 2.22-2.16 (m, 1H), 1.48-1.38 (m,1H), 1.24-1.14 (m, 1H), 0.85 (d, 6H, J = 6.0 Hz). 624

503 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.6 Hz), 8.00- 7.90 (m, 2H), 7.80-7.75 (m, 1H), 7.21(d, 1H, J = 1.6 Hz), 5.99 (d, J = 5.6 Hz), 4.00-3.85 (m, 2H), 3.80-3.65(m, 2H), 3.63-3.40 (m, 4H), 2.92 (s, 3H), 2.75-2.65 (m, 1H), 2.65-2.55(m, 2H), 2.50-2.40 (m, 2H), 2.10-1.95 (m, 3H), 1.95-1.80 (m, 2H), 1.00(d, 6H, J = 6.8 Hz), 0.83-0.70 (m, 4H). 625

503 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1H), 8.29 (s, 1H),7.94-7.90 (m, 2HH), 7.86-7.84 (m, 1H), 7.20 (s, 1H), 5.98 (d, 1H, J =5.6 Hz), 3.92-3.94 (m, 2H), 3.70-3.72 (m, 2H), 3.57- 3.49 (m, 4H),2.95-2.94 (m, 1H), 2.93 (s, 3H), 2.81-2.78 (m, 1H), 2.66-2.63 (m, 1H),2.49- 2.45 (m, 2H), 2.03-2.01 (m, 1H), 1.89-1.87 (m, 1H), 1.74-1.72 (m,2H), 1.34-1.32 (m, 1H), 1.0- 1.01 (m, 6H), 0.78-0.74 (m, 4H). 626

503 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1H), 8.29 (s, 1H),7.94-7.90 (m, 2H), 7.86-7.84 (m, 1H), 7.20 (s, 1H), 5.98 (d, 1H, J = 5.2Hz), 3.92-3.94 (m, 2H), 3.70-3.72 (m, 2H), 3.57- 3.49 (m, 4H), 2.95-2.94(m, 1H), 2.93 (s, 3H), 2.81-2.78 (m, 1H), 2.65-2.63 (m, 1H), 2.49- 2.45(m, 2H), 2.01-2.0 (m, 1H), 1.95-1.89 (m, 1H), 1.76-1.72 (m, 2H),1.32-1.29 (m, 1H), 1.0 (d, 6H, J = 2.0 Hz), 0.78-0.74 (m, 4H). 627

503 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.4 Hz, 1H), 7.70- 7.60 (m, 2H), 7.32-7.21 (m, 2H), 6.88(d, J = 1.9 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 4.67- 4.56 (m, 2H), 3.68(dd, J = 6.6, 3.6 Hz, 4H), 3.54 (dd, J = 6.6, 3.7 Hz, 5H), 3.08 (d, J =11.3 Hz, 2H), 2.83 (p, J = 6.6 Hz, 1H), 2.57 (ddt, J = 12.0, 8.0, 4.1Hz, 1H), 2.41 (dd, J = 13.0, 10.3 Hz, 2H), 1.95-1.71 (m, 5H), 1.15 (d, J= 6.6 Hz, 6H). 628

503 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.35 (s, 1H), 8.15 (d, 1H, J= 1.6 Hz), 7.90 (d, 1H, J = 5.2 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.39 (d,2H, J = 8.4 Hz), 7.00 (d, 1H, J = 1.6 Hz), 6.34 (d, 1H, J = 7.6 Hz),5.98 (d, 1H, J = 5.6 Hz), 3.81- 3.78 (m, 1H), 3.55-3.50 (m, 4H),3.45-3.40 (m, 4H), 2.76-2.73 (m, 1H), 2.65-2.58 (m, 2H), 2.51-2.50 (m,2H), 2.06-2.03 (m, 2H), 1.75- 1.72 (m, 2H), 1.18 (s, 3H), 1.09 (d, 6H, J= 6.4 Hz), 0.97 (d, 6H, J = 6.4 Hz). 629

504 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.8 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.76- 7.64 (m, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.99(d, J = 1.9 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 5.40- 5.24 (m, 1H), 4.78(t, J = 6.9 Hz, 2H), 4.52 (dd, J = 7.6, 5.1 Hz, 2H), 3.63 (d, J = 36.0Hz, 4H), 3.47 (t, J = 5.0 Hz, 4H), 2.88 (d, J = 10.8 Hz, 2H), 2.77-2.62(m, 1H), 2.21 (t, J = 11.4 Hz, 2H), 1.76 (d, J = 12.4 Hz, 2H), 1.69-1.53(m, 2H), 0.99 (d, J = 6.5 Hz, 6H). 630

504 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 6.4 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0Hz), 7.00 (d, 1H, J = 2.0 Hz), 5.99 (d, 1H, J = 6.4 Hz), 5.34-5.31 (m,1H), 4.79 (t, 2H, J = 7.6 Hz), 4.53 (dd, 2H, J = 7.6, 5.6 Hz), 3.71-3.65(m, 2H), 3.65-3.59 (m, 2H), 3.50-3.47 (m, 4H), 2.82-2.78 (m, 2H),2.75-2.69 (m, 2H), 2.20- 2.14 (m, 2H), 1.80-1.75 (m, 1H), 1.75-1.70 (m,1H), 1.60-1.50 (m, 1H), 1.50-1.40 (m, 1H), 0.99-0.96 (m, 6H). 631

504 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 5.33 (quintet,1H, J = 5.2 Hz), 4.78 (t, 2H, J = 7.2 Hz), 4.55-4.45 (dd, 2H, J = 7.2,5.2 Hz), 3.67-3.62 (m, 2H), 3.59-3.53 (m, 2H), 3.50-3.60 (m, 4H),2.85-2.75 (m, 2H), 2.74- 2.63 (m, 2H), 2.20-2.05 (m, 2H), 1.86-1.77 (m,1H), 1.76-1.66 (m, 1H), 1.60-1.36 (m, 2H), 1.00-0.90 (m, 6H). 632

504 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 1.7 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.76- 7./67 (m, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.98(d, J = 1.9 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 3.54 (d, J = 5.6 Hz, 4H),3.43 (dd, J = 6.7, 3.7 Hz, 4H), 2.88 (d, J = 10.9 Hz, 3H), 2.78-2.63 (m,1H), 2.21 (t, J = 11.3 Hz, 2H), 1.76 (d, J = 12.5 Hz, 2H), 1.70-1.51 (m,2H), 1.43 (s, 9H), 0.99 (d, J = 6.6 Hz, 7H). 633

504 1H-NMR (H NMR (400 MHz, CDCl3) δ ppm 78.90 (d, 1H, J = 1.6 Hz), 7.80(d, 1H, J = 5.2 Hz), 7.61 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.4 Hz),6.68 (d, 1H, J = 1.6 Hz), 5.78 (d, 1H, J = 5.2 Hz), 4.39-4.36 (m, 1H),4.02-3.97 (m, 1H), 3.61-3.56 (m, 4H), 3.50-3.46 (m, 4H), 3.11- 3.06 (m,1H), 2.92-2.85 (m, 1H), 2.83-2.74 (m, 1H), 2.72 (heptet, 1H, J = 6.4Hz), 2.53-2.45 (m, 2H), 2.45-2.38 (m, 1H), 1.37 (s, 3H), 1.17 (d, 6H, J= 6.8 Hz), 1.07 (d, 3H, J = 6.4 Hz), 1.02 (d, 3H, J = 6.4 Hz). 634

504 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4Hz), 7.00 (d, 1H, J = 1.6 Hz), 6.31 (d, 1H, J = 8.0 Hz), 5.97 (d, 1H, J= 5.6 Hz), 3.83-3.74 (m, 1H), 3.53-3.51 (m, 4H), 3.44-3.42 (m, 4H),3.13-3.04 (m, 1H), 2.73-2.66 (m, 1H), 2.63- 2.55 (m, 2H), 2.42-2.37 (m,1H), 2.33-2.28 (m, 2H), 2.26-2.22 (m, 1H), 1.21 (s, 3H), 1.07 (d, 6H, J= 6.4 Hz), 1.00-0.95 (m, 6H). 635

505 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.49 (d, 1H, J = 2.0 Hz),8.26 (d, 1H, J = 1.6 Hz), 7.94 (d, 1H, J = 5.6 Hz), 7.86 (d, 1H, J = 8.4Hz), 7.71 (dd, 1H, J = 8.4, 2.0 Hz), 7.16 (d, 1H, J = 1.6 Hz), 6.01 (d,1H, J = 5.6 Hz), 5.35 (quintet, 1H, J = 5.6 Hz), 4.80 (t, 2H, J = 7.2Hz), 4.54 (dd, 2H, J = 7.2, 5.6 Hz), 3.73-3.68 (m, 2H), 3.62-3.55 (m,2H), 3.53-3.45 (m, 4H), 2.85- 2.70 (m, 4H), 2.30-2.10 (m, 2H), 1.90-1.80(m, 1H), 1.78-1.70 (m, 1H), 1.60-1.40 (m, 2H), 1.05-0.90 (m, 6H). 636

505 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.49 (d, 1H, J = 2.0 Hz),8.26 (d, 1H, J = 1.6 Hz), 7.94 (d, 1H, J = 5.6 Hz), 7.86 (d, 1H, J = 8.4Hz), 7.71 (dd, 1H, J = 8.4, 2.0 Hz), 7.16 (d, 1H, J = 1.6 Hz), 6.01 (d,1H, J = 5.6 Hz), 5.35 (quintet, 1H, J = 5.6 Hz), 4.80 (t, 2H, J = 7.2Hz), 4.54 (dd, 2H, J = 7.2, 5.6 Hz), 3.73-3.68 (m, 2H), 3.62-3.55 (m,2H), 3.53-3.45 (m, 4H), 2.85- 2.70 (m, 4H), 2.30-2.10 (m, 2H), 1.90-1.80(m, 1H), 1.78-1.70 (m, 1H), 1.60-1.40 (m, 2H), 1.05-0.90 (m, 6H). 637

505 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.8 Hz, 1H), 7.85(d, J = 5.4 Hz, 1H), 7.78- 7.69 (m, 2H), 7.40-7.29 (m, 2H), 6.98 (d, J =1.8 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H), 5.94 (d, J = 5.5 Hz, 1H), 3.74(h, J = 6.7 Hz, 1H), 3.53- 3.43 (m, 4H), 3.43-3.32 (m, 4H), 2.89 (d, J =13.7 Hz, 5H), 2.76-2.61 (m, 2H), 2.45- 2.37 (m, 1H), 2.16 (ddd, J =12.3, 7.2, 4.7 Hz, 1H), 2.04 (dt, J = 13.1, 7.7 Hz, 1H), 1.06-0.97 (m,12H). 638

505 639

505 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.18 (s, 1H), 7.90 (d, 1H, J= 5.5 Hz), 7.81 (d, 2H, J = 6.0 Hz), 7.48 (d, 2H, J = 8.5 Hz), 7.03 (s,1H), 6.63-6.50 (m, 1H), 5.99 (d, 1H, J = 5.5 Hz), 3.53-3.51 (m, 4H),3.45-3.44 (m, 4H), 3.10- 3.07 (m, 3H), 2.94 (s, 3H), 2.90-2.52 (m, 3H),2.49-2.20 (m, 2H), 1.90-1.40 (m, 4H), 1.06- 1.02 (m, 6H), 1.04 (t, 3H, J= 7.0 Hz). 640

505 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.22- 8.17 (m, 1H), 7.91 (d,2H, J = 5.2 Hz), 7.80- 7.79 (m, 1H), 7.48 (d, 2H, J = 8.4 Hz), 7.03 (s,1H), 6.63-6.50 (m, 1H), 5.99 (d, 1H, J = t5.2 Hz), 3.53-3.51 (m, 4H),3.45-3.44 (m, 4H), 3.10-3.07 (m, 3H), 2.94 (s, 3H), 2.90-2.52 (m, 3H),2.49-2.20 (m, 2H), 1.90-1.40 (m, 2H), 1.30-1.23 (m, 2H), 1.06-1.02 (m,9H). 641

505 1H-NMR (H NMR (500 MHz, 6d-DMSO) δ ppm 8.16 (s, 1H), 7.92 (d, 1H, J= 5.0 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.57 (d, 2H, J = 8.0 Hz), 7.00 (s,1H), 6.00 (d, 1H, J = 5.5 Hz), 4.10 (q, 2H, J =7.0 Hz), 3.61-3.60 (m,4H), 3.48-3.47 (m, 4H), 2.65-2.64 (m, 1H), 2.61-2.60 (m, 3H), 2.39- 2.37(m, 2H), 2.09-2.08 (m, 1H), 1.91 (s, 3H), 1.38 (s, 3H), 1.23 (t, 3H, J =7.0 Hz), 0.94-0.90 (m, 6H). 642

505 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.94 (d, 1H, J = 1.6 Hz), 7.85(d, 1H, J = 5.6 Hz), 7.68- 7.60 (m, 4H), 6.70 (d, 1H, J = 1.6 Hz), 5.85(d, 1H, J = 5.6 Hz), 4.21 (q, 2H, J = 7.2 Hz), 3.80- 3.70 (m, 4H),3.56-3.52 (m, 1H), 3.48-3.42 (m, 4H), 3.42-3.39 (m, 1H), 2.80-2.76 (m,2H), 2.67-2.62 (m, 1H), 2.48-2.44 (m, 1H), 2.24- 2.21 (m, 1H), 2.01 (s,3H), 1.47 (s, 3H), 1.31 (t, 3H, J = 7.2 Hz), 1.05-0.95 (m, 6H). 643

506 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 2.0 Hz),7.92 (d, 1H, J = 5.5 Hz), 7.80 (d, 2H, J = 8.5 Hz), 7.40 (d, 2H, J = 8.5Hz), 7.03 (d, 1H, J = 2.0 Hz), 5.99 (d, 1H, J = 5.5 Hz), 4.10 (q, 2H, J= 7.0 Hz), 3.70-3.56 (m, 4H), 3.50-3.40 (m, 4H), 2.90 (s, 3H), 2.71(heptet, 1H, J = 6.5 Hz), 2.64-2.56 (m, 2H), 2.48-2.42 (m, 2H),2.02-1.94 (m, 2H), 1.92- 1.80 (m, 2H), 1.23 (t, 3H, J = 7.0 Hz), 1.01(d, 6H, J = 6.5 Hz). 644

506 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 1.6 Hz),8.28 (d, 1H, J = 1.6 Hz), 7.94- 7.90 (m, 2H), 7.77 (dd, 1H, J = 8.4, 2.0Hz), 7.17 (d, 1H, J = 1.6 Hz), 6.60 (t, 1H, J = 5.2 Hz), 6.00 (d, 1H, J= 5.6 Hz), 3.55-3.50 (m, 4H), 3.47-3.41 (m, 4H), 3.08 (quintet, 2H, J =5.6 Hz), 2.92 (s, 3H), 2.77-2.70 (m, 1H), 2.68- 2.59 (m, 2H), 2.49-2.40(m, 2H), 2.10-1.95 (m, 2H), 1.95-1.80 (m, 2H), 1.04 (t, 3H, J = 7.2 Hz),1.00 (d, 6H, J = 6.0 Hz). 645

506 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.68 (d, 1H, J = 1.5 Hz),8.29 (d, 1H, J = 1.5 Hz), 7.94- 7.91 (m, 2H), 7.87-7.85 (m, 1H), 7.18(d, 1H, J = 1.5 Hz), 6.61 (t, 1H, J = 5.0 Hz), 6.0 (d, 1H, J = 5.0 Hz),3.54-3.53 (m, 4H), 3.47-3.46 (m, 4H), 3.12-3.07 (m, 2H), 2.99-2.94 (m,1H), 2.94 (s, 3H), 2.83-2.80 (m, 1H), 2.67-2.65 (m, 1H), 2.45-2.40 (m,2H), 1.93-1.88 (m, 1H), 1.77-1.71 (m, 2H), 1.35-1.33 (m, 1H), 1.05 (t,3H, J = 7.0 Hz), 1.04-1.01 (m, 6H). 646

506 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.69 (d, 1H, J = 1.5 Hz),8.27 (d, 1H, J = 1.5 Hz), 7.94- 7.91 (m, 2H), 7.87-7.85 (m, 1H), 7.18(s, 1H), 6.62 (t, 1H, J = 5.0 Hz), 6.00 (d, 1H, J = 5.5 Hz), 3.54-3.53(m, 4H), 3.47-3.46 (m, 4H), 3.09 (quintet, 2H, J = 7.0 Hz), 2.96-2.92(m, 1H), 2.94 (s, 3H), 2.82-2.80 (m, 1H), 2.67-2.64 (m, 1H), 2.47-2.44(m, 2H), 1.92-1.88 (m, 1H), 1.80.175 (m, 1H), 1.75-1.71 (m, 1H), 1.35-1.33 (m, 1H), 1.05 (t, 3H, J = 7.0 Hz), 1.03- 1.00 (m, 6H). 647

507 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.66- 8.45 (m, 1H), 8.36-8.16(m, 1H), 7.97-7.68 (m, 3H), 7.17 (d, J = 1.8 Hz, 1H), 6.01 (d, J = 5.4Hz, 1H), 5.41 (ddd, J = 11.4, 6.3, 5.2 Hz, 1H), 4.98-4.78 (m, 2H), 4.65(dd, J = 7.7, 5.2 Hz, 2H), 3.87-3.60 (m, 5H), 3.54 (dd, J = 6.6, 3.8 Hz,4H), 3.30 (p, J = 1.6 Hz, 1H), 3.17 (q, J = 7.0 Hz, 2H), 3.13-3.01 (m,2H), 2.95 (dt, J = 12.7, 3.5 Hz, 2H), 2.16-2.01 (m, 2H), 1.94 (td, J =13.2, 4.3 Hz, 2H), 1.23-1.08 (m, 3H). 648

507 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 1.8 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H),7.03 (d, J = 1.8 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 5.98 (d, J = 5.5 Hz,1H), 3.77 (h, J = 6.7 Hz, 1H), 3.56-3.47 (m, 4H), 3.42 (dd, J = 6.7, 3.4Hz, 4H), 2.74 (s, 2H), 2.18-1.84 (m, 4H), 1.07 (d, J = 6.6 Hz, 6H), 1.02(d, J = 6.6 Hz, 6H). 649

507 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 7.99 (dd, J = 2.8, 1.7 Hz, 1H),7.88 (d, J = 5.4 Hz, 1H), 7.80 (t, J = 8.4 Hz, 1H), 7.14-7.06 (m, 2H),6.97 (d, J = 1.8 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H), 5.96 (d, J = 5.5 Hz,1H), 3.74 (h, J = 6.7 Hz, 1H), 3.47 (dd, J = 6.8, 3.2 Hz, 4H), 3.39 (d,J = 6.7, 3.3 Hz, 4H), 2.84 (d, J = 10.9 Hz, 2H), 2.74-2.60 (m, 1H), 2.18(t, J = 11.2 Hz, 2H), 1.74 (d, J = 12.2 Hz, 2H), 1.59 (td, J =12.2, 3.7Hz, 2H), 1.03 (d, J = 6.6 Hz, 6H), 0.95 (d, J = 6.6 Hz, 5H). 650

510 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.04 (t, J = 2.2 Hz, 1H),7.95-7.86 (m, 2H), 7.26-7.14 (m, 2H), 7.01 (d, J = 1.8 Hz, 1H), 5.98 (d,J = 5.5 Hz, 1H), 5.34-5.23 (m, 1H), 4.74 (t, J = 6.9 Hz, 2H), 4.48 (dd,J = 7.6, 5.1 Hz, 2H), 3.65 (s, 2H), 3.55 (s, 2H), 3.46 (dd, J = 6.6, 3.7Hz, 4H), 2.88 (s, 3H), 2.84-2.71 (m, 4H), 1.94-1.83 (m, 2H), 1.83-1.70(m, 2H). 651

511 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 9.24 (br. s., 1H), 8.07 (d,1H, J = 2.0 Hz), 7.95 (d, 1H, J = 5.5 Hz), 7.73 (d, 1H, J = 8.5 Hz),7.39 (d, 1H, J = 1.5 Hz), 7.27 (dd, 1H, J = 8.5, 2.0 Hz), 6.91 (d, 1H, J= 2.0 Hz), 6.02 (d, 1H, J = 5.5 Hz), 4.08 (q, 2H, J = 7.5 Hz), 3.64-3.58(m, 4H), 3.57-3.52 (m, 1H), 3.52-3.45 (m, 6H), 3.13-3.07 (m, 2H),2.95-2.90 (m, 1H), 2.07- 2.01 (m, 2H), 1.97-1.89 (m, 2H), 1.30 (d, 6H, J= 6.5 Hz), 1.22 (t, 3H, J = 7.5 Hz). 652

512 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.93 (dd, J = 6.3, 1.8 Hz,1H), 7.83 (dd, J = 5.4, 1.8 Hz, 1H), 7.73-7.61 (m, 2H), 7.33-7.20 (m,2H), 6.87 (dd, J = 6.8, 1.8 Hz, 1H), 6.29-5.88 (m, 2H), 4.34 (td, J =14.4, 3.7 Hz, 2H), 3.74 (s, 5H), 3.51 (t, J = 5.2 Hz, 5H), 3.22-2.95 (m,2H), 2.70-2.50 (m, 2H), 2.01-1.77 (m, 3H), 1.31 (dd, J = 85.1, 6.5 Hz,6H). 653

512 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.49 (d, 1H, J = 2.0 Hz),8.26 (d, 1H, J = 1.5 Hz), 7.93 (d, 1H, J = 5.5 Hz), 7.86 (d, 1H, J = 8.5Hz), 7.71 (dd, 1H, J = 8.5, 2.0 Hz), 7.16 (d, 1H, J = 2.0 Hz), 5.99 (d,1H, J = 5.0 Hz), 3.74-3.69 (m, 2H), 3.69-3.62 (m, 1H), 3.60-3.53 (m,2H), 3.52-3.44 (m, 4H), 3.33-3.24 (m, 3H), 2.84- 2.80 (m, 2H), 2.80-2.76(m, 2H), 2.68-2.60 (m, 2H), 2.26-2.20 (m, 1H), 2.20-2.14 (m, 1H),1.88-1.80 (m, 1H), 1.78-1.70 (m, 1H), 1.60- 1.55 (m, 1H), 1.55-1.47 (m,1H), 1.02-0.90 (m, 6H). 654

512 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.49 (d, 1H, J = 1.6 Hz),8.26 (d, 1H, J = 1.6 Hz), 7.93 (d, 1H, J = 5.6 Hz), 7.86 (d, 1H, J = 8.0Hz), 7.73 (dd, 1H, J = 8.0, 2.0 Hz), 7.16 (d, 1H, J = 1.2 Hz), 5.98 (d,1H, J = 5.6 Hz), 3.74-3.69 (m, 2H), 3.69-3.62 (m, 1H), 3.60-3.53 (m,2H), 3.52-3.44 (m, 4H), 3.33-3.24 (m, 3H), 2.90- 2.70 (m, 4H), 2.68-2.56(m, 2H), 2.40-2.10 (m, 2H), 1.90-1.85 (m, 1H), 1.82-1.75 (m, 1H),1.65-1.40 (m, 2H), 1.10-0.90 (m, 6H). 655

513 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (s, 1H), 8.22 (d, 1H, J= 1.6 Hz), 7.92 (d, 1H, J = 5.6 Hz), 7.84 (d, 2H, J = 8.4 Hz), 8.47 (d,2H, J = 8.4 Hz), 7.06 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz),3.71-3.68 (m, 2H), 3.67-3.63 (m, 3H), 3.56-3.52 (m, 2H), 3.48-3.45 (m,4H), 3.35-3.31 (m, 2H), 3.30-3.25 (m, 2H), 2.96 (s, 3H), 2.65-2.59 (m,2H), 2.53-2.45 (m, 2H), 0.93 (d, 6H, J = 6.4 Hz). 656

516 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.2 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.78 (d, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 8.4Hz), 7.06 (d, 1H, J = 1.2 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.94-3.93 (m,2H), 3.72-3.71 (m, 2H), 3.55-3.48 (m, 4H), 3.19-3.16 (m, 1H), 3.05- 3.00(m, 1H), 2.88-2.80 (m, 2H), 2.69-2.64 (m, 1H), 2.43-2.33 (m, 2H),2.05-2.00 (m, 1H), 1.82-1.69 (m, 3H), 1.41-1.29 (m, 1H), 1.05- 1.02 (m,9H), 0.79-0.74 (m, 4H). 657

516 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.78 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 8.8Hz), 7.06 (d, 1H, J = 1.2 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.94-3.92 (m,2H), 3.71-3.70 (m, 2H), 3.54-3.48 (m, 4H), 3.32-3.31 (m, 1H), 3.23- 3.19(m, 1H), 3.03-2.99 (m, 1H), 2.87-2.77 (m, 2H), 2.68-2.65 (m, 1H),2.42-2.41 (m, 1H), 2.05-2.01 (m, 1H), 1.81-1.73 (m, 3H), 1.37- 1.35 (m,1H), 1.05-0.99 (m, 9H), 0.79-0.73 (m, 4H). 658

516 1H-NMR (H NMR (400 MHz, 4d-MeOD) δ ppm 8.00 (d, 1H, J = 2.0 Hz),7.86 (d, 1H, J = 5.2 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.0Hz), 6.95 (d, 1H, J = 1.6 Hz), 6.01 (d, 1H, J = 5.6 Hz), 4.05-4.04 (m,2H), 3.87-3.86 (m, 2H), 3.64-3.63 (m, 2H), 3.56-3.55 (m, 2H), 3.15 (q,2H, J = 6.8 Hz), 3.01-2.85 (m, 5H), 2.24-2.20 (m, 2H), 2.11-2.03 (m,3H), 1.22 (d, 6H, J = 6.4 Hz), 1.15 (t, 3H, J = 6.8 Hz), 0.95-0.93 (m,2H), 0.89-0.86 (m, 2H). 659

516 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.23 (br.s, 1H), 8.18 (d, 1H,J = 1.5 Hz), 7.90 (d, 1H, J = 5.0 Hz), 7.78 (d, 2H, J = 8.5 Hz), 7.40(d, 2H, J = 8.5 Hz), 6.98 (d, 1H, J = 1.0 Hz), 5.96 (d, 1H, J = 5.5 Hz),4.63-4.62 (m, 1H), 4.20- 4.19 (m, 1H), 3.93-3.92 (m, 2H), 2.89 (s, 3H),2.75-2.74 (m, 1H), 2.63-2.62 (m, 2H), 2.56- 2.55 (m, 2H), 2.01-1.98 (m,4H), 1.90-1.87 (m, 2H), 1.41-1.40 (m, 2H), 1.25-1.21 (m, 3H), 1.04-1.01(m, 6H), 0.78-0.76 (m, 4H). 660

517 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.60 (d, 1H, J = 1.6 Hz),8.31 (d, 1H, J = 1.6 Hz), 7.95 (s, 1H), 7.93 (d, 1H, J = 1.6 Hz), 7.80(dd, 1H, J = 8.4, 2.4 Hz), 7.22 (d, 1H, J = 2.0 Hz), 6.00 (d, 1H, J =5.6 Hz), 4.56 (t, 2H, J = 6.4 Hz), 4.45 (t, 2H, J = 6.4 Hz), 4.00-3.80(m, 2H), 3.70-3.55 (m, 2H), 3.60-3.55 (m, 2H), 3.54- 3.48 (m, 2H),3.47-3.40 (m, 1H), 2.93 (s, 3H), 2.60-2.52 (m, 2H), 2.22-2.10 (m, 2H),2.08- 1.88 (m, 5H), 0.82-0.70 (m, 4H). 661

517 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.88 (d, J = 5.4Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.99 (s,1H), 6.77 (s, 1H), 5.97 (d, J = 5.4 Hz, 1H), 4.59 (dd, J = 7.8, 6.0 Hz,2H), 4.29 (t, J = 6.0 Hz, 2H), 3.51 (s, 4H), 3.44 (s, 4H), 3.25-2.94 (m,2H), 1.95-1.63 (m, 4H), 1.11 (s, 6H). 662

517 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.5 Hz),8.30 (d, 1H, J = 1.5 Hz), 7.94 (d, 1H, J = 5.5 Hz), 7.92 (s, 1H), 7.79(dd, 1H, J = 8.5, 2.5 Hz), 7.21 (d, 1H, J = 1.5 Hz), 6.00 (d, 1H, J =5.5 Hz), 3.96-3.94 (m, 2H), 3.72- 3.71 (m, 2H), 3.60-3.55 (m, 2H),3.55-3.50 (m, 2H), 3.08 (q, 2H, J = 7.0 Hz), 2.70-2.64 (m, 1H),2.62-2.58 (m, 2H), 2.59-2.54 (m, 2H), 2.04-2.00 (m, 3H), 1.99-1.90 (m,2H), 1.09 (t, 3H, J = 7.0 Hz), 1.01 (d, 6H, J = 5.5 Hz), 0.78- 0.72 (m,4H). 663

517 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 1.7 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H),6.98 (d, J = 1.8 Hz, 1H), 6.20 (d, J = 8.3 Hz, 1H), 5.97 (d, J = 5.5 Hz,1H), 3.58-3.47 (m, 5H), 3.42 (t, J = 5.0 Hz, 4H), 2.88 (d, J = 10.8 Hz,2H), 2.79-2.62 (m, 1H), 2.21 (t, J = 11.4 Hz, 2H), 1.76 (d, J = 12.2 Hz,2H), 1.69-1.51 (m, 3H), 1.00 (t, J = 6.4 Hz, 9H), 0.84 (dd, J = 6.7, 4.1Hz, 6H). 664

517 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 1.8 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.77- 7.66 (m, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.99(d, J = 1.8 Hz, 1H), 6.49 (t, J = 6.2 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H),3.62-3.47 (m, 4H), 3.43 (dd, J = 6.7, 3.6 Hz, 4H), 2.89 (dd, J = 14.5,8.5 Hz, 4H), 2.70 (p, J = 6.6 Hz, 1H), 2.52- 2.35 (m, 1H), 2.20 (td, J =11.5, 2.3 Hz, 2H), 1.83-1.70 (m, 2H), 1.61 (qd, J = 12.2, 3.7 Hz, 2H),0.98 (d, J = 6.6 Hz, 6H), 0.83 (s, 8H). 665

518 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.8 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.75- 7.68 (m, 2H), 7.28-7.20 (m, 2H), 6.99 (d, J =1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.65 (dd, J = 8.0, 1.6 Hz, 2H),4.39-4.35 (m, 2H), 4.24 (d, J = 6.3 Hz, 2H), 3.61 (s, 4H), 3.46 (dd, J =6.7, 3.7 Hz, 4H), 3.29-3.21 (m, 1H), 2.88 (d, J = 10.9 Hz, 2H),2.74-2.65 (m, 1H), 2.21 (t, J = 11.3 Hz, 2H), 1.76 (d, J = 12.3 Hz, 2H),1.69- 1.54 (m, 2H), 0.99 (d, J = 6.5 Hz, 6H). 666

518 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 1.8 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.73- 7.68 (m, 2H), 7.26-7.19 (m, 2H), 6.97 (d, J =1.9 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 5.17 (ddt, J = 6.5, 4.3, 1.9 Hz,1H), 3.82-3.68 (m, 4H), 3.58 (d, J = 5.5 Hz, 4H), 3.45 (dd, J = 6.6, 3.7Hz, 4H), 2.91 (d, J = 11.1 Hz, 2H), 2.75 (p, J = 6.5 Hz, 1H), 2.30-2.21(m, 2H), 2.12 (dtd, J = 13.6, 8.3, 6.3 Hz, 1H), 1.92 (dt, J = 11.9, 5.3Hz, 1H), 1.77 (d, J = 12.1 Hz, 2H), 1.63 (qd, J = 12.2, 3.7 Hz, 2H),1.00 (d, J = 6.5 Hz, 6H). 667

518 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 1.8 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.75- 7.67 (m, 2H), 7.26-7.20 (m, 2H), 6.98 (d, J =1.8 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 5.17 (ddt, J = 6.5, 4.3, 1.9 Hz,1H), 3.83-3.68 (m, 4H), 3.58 (d, J = 5.5 Hz, 4H), 3.45 (d, J = 5.7 Hz,4H), 2.96 (d, J = 11.2 Hz, 2H), 2.83 (p, J = 6.6 Hz, 1H), 2.40-2.27 (m,2H), 2.12 (dtd, J = 13.6, 8.3, 6.3 Hz, 1H), 1.97-1.88 (m, 1H), 1.84-1.75(m, 2H), 1.74-1.60 (m, 2H), 1.03 (d, J = 6.6 Hz, 6H). 668

518 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ 8.15 (s, 1H), 7.91 (d, 1H, J =5.0 Hz), 7.73 (d, 2H, J = 8.5 Hz), 7.37 (d, 2H, J = 8.5 Hz), 7.00 (s,1H), 6.00 (d, 1H, J = 5.0 Hz), 4.43-4.40 (m, 1H), 3.88-3.84 (m, 1H),3.62-3.64 (m, 4H), 3.46- 3.48 (m, 4H), 3.32-3.30 (m, 4H), 2.81-2.79 (m,1H), 2.66-2.64 (m, 2H), 2.46-2.38 (m, 2H), 2.08-1.98 (m, 2H), 1.76-1.68(m, 2H), 1.17 (s, 3H), 0.94 (d, 1H, J = 6.0 Hz). 669

518 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.25 (s, 1H), 8.14 (d, 1H, J= 2.0 Hz), 7.89 (d, 1H, J = 5.5 Hz), 7.71 (d, 2H, J = 8.0 Hz), 7.26 (d,2H, J = 8.0 Hz), 6.93 (d, 1H, J = 1.5 Hz), 5.97 (d, 1H, J = 5.0 Hz),5.36-5.33 (m, 1H), 4.79 (t, 2H, J = 7.0 Hz), 4.53-4.51 (m, 2H),3.93-3.91 (m, 2H), 3.25-3.21 (m, 2H), 3.07-3.03 (m, 1H), 2.94-2.92 (m,2H), 2.78-2.77 (m, 1H), 2.28- 2.27 (m, 2H), 2.00-1.99 (m, 1H), 1.79-1.77(m, 2H), 1.67-1.64 (m, 2H), 1.34-1.32 (m, 2H), 1.25-1.20 (m, 3H),1.06-1.01 (m, 6H). 670

518 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 1.7 Hz, 1H), 7.90(d, J = 5.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H),7.01 (d, J = 1.9 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 3.63 (s, 5H), 3.48(d, J = 5.6 Hz, 6H), 2.01 (s, 6H), 1.28 (s, 8H), 0.93 (s, 10H) 671

518 1H-NMR (H NMR (500 MHz, 6d-DMSO) δ ppm 8.15 (s, 1H), 7.90 (d, 1H, J= 5.5 Hz), 7.74 (d, 2H, J = 8.0 Hz), 7.57 (d, 2H, J = 8.0 Hz), 6.99 (d,1H, J = 1.0 Hz), 6.32 (d, 1H, J = 7.5 Hz), 6.00 (d, 1H, J = 5.5 Hz),3.79-3.78 (m, 1H), 3.54-3.52 (m, 4H), 3.45-3.43 (m, 4H), 2.75-2.74 (m,1H), 2.62-2.61 (m, 3H), 2.37-2.36 (m, 2H), 2.09- 2.08 (m, 1H), 1.92 (s,3H), 1.39 (s, 3H), 1.08 (d, 6H, J = 6.5 Hz), 0.95-0.90 (m, 6H). 672

518 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 7.94 (d, 1H, J = 1.6 Hz), 7.84(d, 1H, J = 6.4 Hz), 7.68- 7.60 (m, 4H), 6.72 (d, 1H, J =1.6 Hz), 5.83(d, 1H, J = 6.4 Hz), 4.28 (d, 1H, J = 7.2 Hz), 4.10- 4.00 (m, 1H),3.65-3.58 (m, 4H), 3.56-3.46 (m, 4H), 3.45-3.40 (m, 1H), 2.80-2.75 (m,2H), 2.74-2.70 (m, 1H), 2.50-2.45 (m, 1H), 2.25- 2.21 (m, 1H), 2.02 (s,3H), 1.48 (s, 3H), 1.20 (d, 6H, J = 6.4 Hz), 1.05-0.95 (m, 6H). 673

519 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 8.0Hz), 7.03 (d, 1H, J = 1.6 Hz), 6.62 (t, 1H, J = 5.2 Hz), 5.99 (d, 1H, J= 5.2 Hz), 3.53-3.51 (m, 4H), 3.45-3.43 (m, 4H), 3.23-3.18 (m, 1H),3.12-3.07 (m, 2H), 3.01-2.99 (m, 1H), 2.89- 2.77 (m, 2H), 2.67-2.65 (m,1H), 2.45-2.40 (m, 2H), 1.81-1.70 (m, 3H), 1.40-1.30 (m, 1H), 1.05-0.99(m, 12H). 674

519 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.77 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 8.0Hz), 7.03 (d, 1H, J = 1.2 Hz), 6.62 (s, 1H), 5.98 (d, 1H, J = 5.6 Hz),3.53-3.52 (m, 4H), 3.45-3.43 (m, 4H), 3.34-3.33 (m, 1H), 3.23-3.21 (m,1H), 3.12-3.00 (m, 3H), 2.87-2.77 (m, 2H), 2.68- 2.65 (m, 1H), 2.41-2.40(m, 1H), 1.81-1.73 (m, 3H), 1.37-1.35 (m, 1H), 1.06-0.99 (m, 12H). 675

519 1H-NMR (H NMR (400 MHz, 4d-MeOD) δ ppm 7.99 (d, 1H, J = 1.6 Hz),7.86 (d, 1H, J = 5.6 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.48 (d, 2H, J = 8.4Hz), 6.92 (d, 1H, J = 1.6 Hz), 6.01 (d, 1H, J = 5.2 Hz), 3.67-3.65 (m,4H), 3.56-3.54 (m, 4H), 3.24 (q, 2H, J = 7.2 Hz), 3.17 (d, 2H, J = 6.8Hz), 3.11-3.10 (m, 2H), 3.07-2.06 (m, 2H), 2.32-2.28 (m, 2H), 2.12-2.11(m, 2H), 1.29 (d, 6H, J = 6.4 Hz), 1.18-1.14 (m, 7H). 676

519 677

519 678

520 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.4Hz), 7.0 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 5.34 (quintet,1H, J = 5.2 Hz), 4.80 (t, 2H, J = 7.2 Hz), 4.54 (dd, 2H, J = 7.2, 5.6Hz), 4.54-4.49 (m, 1H), 3.69-3.65 (m, 2H), 3.65- 3.60 (m, 3HH),3.51-3.49 (m, 4H), 2.89-2.75 (m, 3H), 2.65-2.59 (m, 1H), 2.33-2.24 (m,2H), 1.94-1.92 (m, 1H), 1.53-1.50 (m, 1H), 0.98 (s, 6H). 679

520 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.25 (s, 1H), 8.16 (d, 1H, J= 1.6 Hz), 7.91 (d, 1H, J = 5.2 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.28 (d,2H, J = 8.0 Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.2 Hz),5.34 (quintet, 1H, J = 5.2 Hz), 4.80 (t, 2H, J = 6.8 Hz), 4.54 (dd, 2H,J = 7.2, 5.2 Hz), 3.79-3.70 (m, 5H), 3.57-3.50 (m, 4H), 2.90-2.78 (m,4H), 2.69-2.60 (m, 1H), 2.41- 2.32 (m, 2H), 1.95-1.92 (m, 1H), 1.61-1.49(m, 1H), 1.01-0.99 (m, 6H). 680

520 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.68- 7.62 (m, 2H), 7.37-7.33 (m, 1H), 7.13(d, 1H, J = 1.6 Hz), 5.96 (d, 1H, J = 5.2 Hz), 3.93-3.91 (m, 2H),3.67-3.66 (m, 2H), 3.56-3.47 (m, 4H), 2.96 (s, 3H), 2.67-2.57 (m, 3H),2.49-2.45 (m, 2H), 2.13-1.95 (m, 5H), 0.98 (d, 6H, J = 6.8 Hz),0.78-0.73 (m, 4H). 681

520 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 5.00-4.70 (m,1H), 4.00-3.90 (m, 2H), 3.75-3.65 (m, 2H), 3.61-3.49 (m, 2H), 3.37- 3.40(m, 2H), 2.88 (s, 3H), 2.72-2.65 (m, 2H), 2.60-2.54 (m, 2H), 2.48-2.42(m, 2H), 2.00- 1.92 (m, 2H), 1.90-1.76 (m, 2H), 1.50-1.36 (m, 1H),1.24-1.10 (m, 1H), 0.99 (d, 6H, J = 6.4 Hz). 682

520 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.27 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.68- 7.62 (m, 2H), 7.36 (t, 1H, J = 8.4 Hz),7.14 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.94- 3.92 (m, 2H),3.72-3.70 (m, 2H), 3.56-3.51 (m, 2H), 3.50-3.45 (m, 2H), 2.97 (s, 3H),2.69-2.65 (m, 1H), 2.60-2.56 (m, 2H), 2.46-2.44 (m, 2H), 2.14-2.10 (m,2H), 2.04-2.00 (m, 1H), 1.98- 1.92 (m, 2H), 1.00 (d, 6H, J = 6.8 Hz),0.78- 0.74 (m, 4H). 683

520 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.65- 7.63 (m, 2H), 7.51 (t, 1H, J = 8.4 Hz),7.14 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.93- 3.80 (m, 2H),3.72-3.70 (m, 2H), 3.65-3.54 (m, 2H), 3.55-3.46 (m, 2H), 3.03-3.00 (m,1H), 2.98 (s, 3H), 2.80-2.76 (m, 1H), 2.68-2.64 (m, 1H), 2.50-2.42 (m,2H), 2.07-2.00 (m, 2H), 1.76-1.71 (m, 2H), 1.39-1.36 (m, 1H), 1.01- 0.99(m, 6H), 0.79-0.73 (m, 4H). 684

520 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.65- 7.63 (m, 2H), 7.52 (t, 1H, J = 8.l4 Hz),7.14 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.93- 3.80 (m, 2H),3.72-3.70 (m, 2H), 3.65-3.54 (m, 2H), 3.55-3.46 (m, 2H), 3.30 (s, 3H),2.80-2.76 (m, 1H), 2.68-2.64 (m, 1H), 2.50-2.42 (m, 3H), 2.07-2.00 (m,2H), 1.76-1.71 (m, 2H), 1.39- 1.36 (m, 1H), 1.01-0.99 (m, 6H), 0.79-0.73(m, 4H). 685

520 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.29 (s, 1H), 8.19 (d, 1H, J= 1.6 Hz), 7.91 (d, 1H, J = 5.2 Hz), 7./80 (d, 2H, J = 8.4 Hz), 7.39 (d,2H, J = 8.4 Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz),4.82 (heptet, 1H. J = 6.4 Hz), 3.60-3.59 (m, 4H), 3.46-3.45 (m, 4H),2.90 (s, 3H), 2.84 (heptet, 1H, J = 6.8 Hz), 2.74-2.71 (m, 2H),2.64-2.58 (m, 2H), 2.04-1.97 (m, 2H), 1.96-1.91 (m, 2H), 1.22 (d, 6H, J= 6.4 Hz), 1.05 (d, 6H, J = 6.8 Hz). 686

520 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.66 (d, 1H, J = 1.6 Hz),8.27 (d, 1H, J = 1.6 Hz), 7.93- 7.90 (m, 2H), 7.86-7.84 (m, 1H), 7.16(d, 1H, J = 1.6 Hz), 6.30 (d, 1H, J = 7.6 Hz), 5.99 (d, 1H, J = 5.6 Hz),3.82-3.73 (m, 1H), 3.53-3.52 (m, 4H), 3.45-3.44 (m, 4H), 2.98-2.88 (m,1H), 2.93 (s, 3H), 2.83-2.78 (m, 1H), 2.66-2.63 (m, 1H), 2.46-2.40 (m,2H), 1.93-1.87 (m, 1H), 1.75-1.68 (m, 2H), 1.37-1.33 (m, 1H), 1.08 (d,6H, J = 6.8 Hz), 1.02-0.99 (m, 6H). 687

520 1H-NMR (H-NMR (400 MHz, DMSO-d6) δ ppm 8.66 (d, 1H, J = 1.6 Hz),8.27 (d, 1H, J = 1.6 Hz), 7.93- 7.90 (m, 2H), 7.86-7.84 (m, 1H), 7.16(d, 1H, J = 2.0 Hz), 6.30 (d, 1H, J = 7.2 Hz), 5.99 (d, 1H, J = 5.6 Hz),3.82-3.74 (m, 1H), 3.53-3.52 (m, 4H), 3.45-3.44 (m, 4H), 2.98-2.89 (m,1H), 2.93 (s, 3H), 2.83-2.75 (m, 1H), 2.66-2.63 (m, 1H), 2.46-2.43 (m,2H), 1.93-1.84 (m, 1H), 1.78-1.65 (m, 2H), 1.38-1.29 (m, 1H), 1.08 (d,6H, J = 6.4 Hz), 1.02-0.99 (m, 6H). 688

520 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.2 Hz), 7.94- 7.90 (m, 2H), 7.77 (dd, 1H, J = 8.0, 2.0Hz), 7.17 (d, 1H, J = 1.6 Hz), 6.30 (d, 1H, J = 7.6 Hz), 6.00 (d, 1H, J= 5.2 Hz), 3.82-3.75 (m, 1H), 3.55-3.50 (m, 4H), 3.47-3.42 (m, 4H), 2.92(s, 3H), 2.92 (s, 3H), 2.77-2.70 (m, 1H), 2.60-2.50 (m, 1H), 2.49-2.40(m, 1H), 2.10- 1.95 (m, 2H), 1.95-1.80 (m, 2H), 1.08 (d, 6H, J = 6.4Hz), 1.00 (d, 6H, J = 6.4 Hz). 689

521 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.46 (d, 1H, J = 5.2 Hz),8.19 (s, 1H), 7.98 (d, 1H, J = 5.2 Hz), 7.29 (t, 1H, J = 5.2 Hz), 7.21(s, 1H), 6.02 (d, 1H, J = 5.6 Hz), 3.96-3.94 (m, 2H), 3.72-3.71 (m, 2H),3.62-3.60 (m, 2H), 3.51- 3.50 (m, 2H), 3.04 (s, 3H), 2.74-2.66 (m, 3H),2.55-2.50 (m, 1H), 2.18-2.14 (m, 2H), 2.07- 2.01 (m, 2H), 1.02 (d, 6H, J= 6.0 Hz), 0.78- 0.74 (m, 4H). 690

522 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 1.5 Hz),7.92 (d, 1H, J = 5.5 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.50 (d, 2H, J = 8.5Hz), 7.05 (d, 1H, J = 2.0 Hz), 5.99 (d, 1H, J = 5.5 Hz), 5.34 (quintet,1H, J = 5.5 Hz), 4.79 (t, 2H, J = 7.5 Hz), 4.53 (dd, 2H, J = 7.5, 5.5Hz), 3.78-3.74 (m, 2H), 3.62-3.55 (m, 2H), 3.55- 3.40 (m, 4H), 2.83-2.75(m, 2H), 2.75-2.70 (m, 1H), -2.68-2.58 (m, 1H), 2.38-2.27 (m, 1H),2.08-2.00 (m, 1H), 1.98-1.90 (m, 1H), 1.87- 1.75 (m, 1H), 1.61-1.51 (m,1H), 1.03-0.90 (m, 6H). 691

522 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.20 (d, 1H, J = 1.5 Hz),7.92 (d, 1H, J = 5.5 Hz), 7.82 (d, 2H, J = 8.5 Hz), 7.50 (d, 2H, J = 8.5Hz), 7.05 (d, 1H, J = 2.0 Hz), 5.99 (d, 1H, J = 5.5 Hz), 5.34 (quintet,1H, J = 5.5 Hz), 4.79 (t, 2H, J = 7.5 Hz), 4.53 (dd, 2H, J = 7.5, 5.5Hz), 3.78-3.74 (m, 2H), 3.62-3.55 (m, 2H), 3.55- 3.40 (m, 4H), 2.83-2.75(m, 2H), 2.75-2.70 (m, 1H), -2.68-2.58 (m, 1H), 2.38-2.37 (m, 1H),2.08-2.00 (m, 1H), 1.98-1.90 (m, 1H), 1.87- 1.75 (m, 1H), 1.61-1.51 (m,1H), 1.03-0.90 (m, 6H). 692

522 1H-NMR (H NMR (500 MHz, 6d-DMSO) δ ppm 8.24 (d, 1H, J = 1.5 Hz),7.92 (d, 1H, J = 5.5 Hz), 7.66 (d, 1H, J = 11.5 Hz), 7.61 (d, 1H, J =7.5 Hz), 7.38 (t, 1H, J = 6.5 Hz), 7.09 (d, 1H, J = 1.5 Hz), 6.00 (d,1H, J = 5.5 Hz), 5.35 (quintet, 1H, J = 5.5 Hz), 4.80 (t, 2H, J = 7.5Hz), 4.54 (dd, 2H, J = 7.5, 5.5 Hz), 3.70-3.60 (m, 2H), 3.60-3.55 (m,2H), 3.50-3.48 (m, 4H), 3.10- 2.98 (m, 1H), 2.82-2.81 (m, 2H), 2.21-2.19(m, 2H), 1.79-1.76 (m, 2H), 1.56-1.55 (m, 2H) ), 1.00-0.99 (m, 6H). 693

522 1H-NMR (H NMR (500 MHz, 6d-DMSO) δ ppm 8.24 (d, 1H, J = 1.5 Hz),7.92 (d, 1H, J = 5.5 Hz), 7.66 (d, 1H, J = 11.5 Hz), 7.61 (d, 1H, J =7.5 Hz), 7.38 (t, 1H, J = 6.5 Hz), 7.09 (d, 1H, J = 1.5 Hz), 6.00 (d,1H, J = 5.5 Hz), 5.35 (quintet, 1H, J = 5.5 Hz), 4.80 (t, 2H, J = 7.5Hz), 4.54 (dd, 2H, J 7.5, 5.5 Hz), 3.70-3.60 (m, 2H), 3.60-3.55 (m, 2H),3.50-3.48 (m, 4H), 3.10- 2.98 (m, 1H), 2.82-2.81 (m, 2H), 2.21-2.19 (m,2H), 1.79-1.76 (m, 2H), 1.56-1.55 (m, 2H) ), 1.00-0.99 (m, 6H). 694

552 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 2.8, 1.7 Hz, 1H),7.90 (d, J = 5.4 Hz, 1H), 7.81 (t, J = 8.4 Hz, 1H), 7.17-7.05 (m, 2H),6.98 (d, J = 1.8 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 5.29 (tt, J = 6.3,5.1 Hz, 1H), 4.81-4.68 (m, 2H), 4.48 (dd, J = 7.6, 5.1 Hz, 2H), 3.59 (d,J = 40.5 Hz, 4H), 3.45 (dd, J = 6.7, 3.7 Hz, 4H), 2.84 (d, J = 10.9 Hz,2H), 2.72-2.60 (m, 1H), 2.22-2.10 (m, 2H), 1.74 (d, J = 12.4 Hz, 2H),1.67-1.49 (m, 2H), 0.95 (d, J = 6.6 Hz, 6H). 695

523 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.73 (s, 1H), 8.31 (s, 1H),7.96-7.92 (m, 3H), 7.21 (s, 1H), 6.06-6.01 (m, 1H), 5.37-5.32 (m, 1H),4.81-4.78 (m, 2H), 4.55-4.53 (m, 2H), 3.74- 3.69 (m, 2H), 3.68-3.62 (m,2H), 3.52-3.49 (m, 4H), 2.90-2.85 (m, 2H), 2.69-2.64 (m, 2H), 2.44-2.36(m, 1H), 2.12-1.98 (m, 1H), 1.96- 1.93 (m, 1H), 1.80-1.75 (m, 1H),1.61-1.53 (m, 1H), 1.01-0.98 (m, 6H). 696

523 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.72 (s, 1H), 8.31 (d, 1H, J= 1.6 Hz), 7.97-7.91 (m, 3H), 7.21 (s, 1H), 6.02 (d, 1H, J = 5.6 Hz),5.34 (quintet, 1H, J = 5.6 Hz), 4.80 (d, 2H, J = 7.2 Hza), 4.53 (dd, 2H,J 7.2, 5.2 Hz), 3.75- 3.70 (m, 2H), 3.65-3.60 (m, 2H), 3.56-3.46 (m,4H), 2.85-2.79 (m, 2H), 2.75-2.68 (m, 2H), 2.41-2.33 (m, 1H), 2.15-2.09(m, 1H), 2.01- 1.73 (m, 2H), 1.60-1.53 (m, 1H), 1.02-0.97 (m, 6H). 697

523 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.25 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.68- 7.62 (m, 2H), 7.37-7.32 (m, 1H), 7.10(s, 1H), 6.59 (t, 1H, J = 5.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 3.52-3.51(m, 4H), 3.44-3.43 (m, 4H), 3.10-3.04 (m, 2H), 2.96 (s, 3H), 2.67-2.57(m, 3H), 2.49-2.45 (m, 2H), 2.13-2.09 (m, 2H), 2.01-1.92 (m, 2H), 1.03(t, 3H, J = 7.2 Hz), 0.99 (d, 6H, J = 6.8 Hz). 698

523 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.65- 7.63 (m, 2H), 7.52 (t, 1H, J = 8.4 Hz),7.11 (d, 1H, J = 1.6 Hz), 6.62 (t, 1H, J = 5.6 Hz), 5.99 (d, 1H, J = 5.6Hz), 3.56-3.52 (m, 4H), 3.46- 3.44 (m, 4H), 3.10-3.08 (m, 2H), 3.05-3.00(m, 1H), 2.99 (s, 3H), 2.80-2.77 (m, 1H), 2.77-2.68 (m, 1H), 2.50-2.42(m, 2H), 2.08-2.07 (m, 1H), 1.76-1.70 (m, 2H), 1.37-1.36 (m, 1H), 1.06-1.00 (m, 9H). 699

523 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.65- 7.63 (m, 2H), 7.52 (t, 1H, J = 8.4 Hz),7.11 (d, 1H, J = 1.6 Hz), 6.61 (t, 1H, J = 5.6 Hz), 5.98 (d, 1H, J = 5.6Hz), 3.56-3.52 (m, 4H), 3.46- 3.44 (m, 4H), 3.10-3.08 (m, 2H), 3.05-3.00(m, 1H), 2.99 (s, 3H), 2.80-2.77 (m, 1H), 2.77-2.68 (m, 1H), 2.50-2.42(m, 2H), 2.08-2.07 (m, 1H), 1.76-1.70 (m, 2H), 1.37-1.36 (m, 1H), 1.06-1.00 (m, 9H).= 700

524 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 9.24 (br. s., 1H), 8.07 (d,1H, J = 1.0 Hz), 7.95 (d, 1H, J = 5.5 Hz), 7.73 (d, 1H, J = 7.5 Hz),7.39 (s, 1H), 7.27 (d, 1H, J = 7.0 Hz), 6.91 (d, 1H, J = 1.5 Hz), 6.31(d, 1H, J = 7.0 Hz), 6.02 (d, 1H, J = 6.0 Hz), 3.80-3.76 (m, 1H),3.55-3.51 (m, 6H), 3.51-3.49 (m, 1H), 3.49-3.42 (m, 4H), 3.13-3.07 (m,2H), 2.95-2.90 (m, 1H), 2.11- 2.08 (m, 2H), 1.97-1.90 (m, 2H), 1.29 (d,6H, J = 6.5 Hz), 1.07 (d, 6H, J = 6.5 Hz). 701

524 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.03 (t, J = 2.2 Hz, 1H),7.93-7.84 (m, 2H), 7.25-7.16 (m, 2H), 7.00 (d, J = 1.8 Hz, 1H), 5.97 (d,J = 5.5 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.55 (d, J = 5.8 Hz, 4H),3.43 (dd, J = 6.7, 3.7 Hz, 4H), 2.87 (s, 3H), 2.60 (dd, J = 32.7, 8.3Hz, 3H), 1.93 (d, J = 13.0 Hz, 2H), 1.81 (t, J = 11.6 Hz, 2H), 1.17 (t,J = 7.1 Hz, 3H), 0.95 (d, J = 6.5 Hz, 6H). 702

526 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.34 (s, 1H), 8.07 (d, 1H, J= 2.0 Hz), 7.77 (d, 1H, J = 5.2 Hz), 7.73-7.68 (m, 2H), 7.04 (d, 1H, J =1.6 Hz), 5.87 (d, 1H, J = 5.6 Hz), 3.77-3.69 (m, 4H), 3.48-3.42 (m, 4H),3.39-3.33 (m, 1H), 3.31-3.14 (m, 1H), 2.94-2.88 (m, 1H), 2.79- 2.73 (m,1H), 2.71-2.64 (m, 1H), 2.57-2.46 (m, 3H), 2.31-2.23 (m, 1H), 2.09-2.04(m, 2H), 1.88-1.81 (m, 1H), 1.79-1.70 (m, 2H), 1.62- 1.52 (m, 2H),1.48-1.39 (m, 2H), 1.08 (s, 6H). 703

526 1H-NMR (H-NMR (400 MHz, CDCl3) δ ppm 8.52 (d, 1H, J = 2.0 Hz), 8.13(d, 1H, J = 1.6 Hz), 7.87 (d, 1H, J = 5.2 Hz), 7.64 (dd, 1H, J = 8.0,2.0 Hz), 7.59 (d, 1H, J = 8.0 Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.83 (d,1H, J = 5.6 Hz), 3.88-3.83 (m, 2H), 3.77-3.72 (m, 2H), 3.57-3.52 (m,2H), 3.47-3.42 (m, 2H), 3.41-3.37 (m, 1H), 3.23- 3.18 (m, 1H), 2.98-2.93(m, 1H, 2.78-2.73 (m, 1H), 2.60-2.47 (m, 4H), 2.45-2.38 (m, 1H),2.26-2.23 (m, 2H), 1.91-1.85 (m, 3H), 1.71- 1.65 (m, 2H), 1.64-1.59 (m,2H), 1.17-1.13 (m, 6H). 704

527 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.13 (d, J = 1.7Hz, 1H), 7.89 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.25 (d, J= 8.1 Hz, 2H), 6.98 (d, J = 1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.86(p, J = 7.3 Hz, 1H), 3.58 (d, J = 17.1 Hz, 5H), 3.46 (t, J = 5.2 Hz,4H), 3.06 (t, J = 8.8 Hz, 1H), 2.93 (d, J = 11.2 Hz, 2H), 2.83-2.70 (m,2H), 2.59 (d, J = 7.0 Hz, 1H), 2.42-2.22 (m, 3H), 1.78 (d, J = 12.0 Hz,2H), 1.73-1.57 (m, 2H), 0.99 (d, J = 8.3 Hz, 4H). 705

527 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.19 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.06 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.2 Hz), 4.00-3.90 (m,2H), 3.76-3.68 (m, 2H), 3.64-3.52 (m, 2H), 3.51-3.40 (m, 2H), 3.00- 2.90(m, 1H), 2.88 (s, 3H), 2.70 (heptet, 1H, J = 6.4 Hz), 2.62-2.54 (m, 2H),2.48-2.42 (m, 2H), 2.15-2.05 (m, 1H), 2.00-1.92 (m, 2H), 1.90-1.78 (m,2H), 1.50-1.40 (m, 1H), 1.38- 1.30 (m, 1H), 0.99 (d, 6H, J = 6.4 Hz).706

527 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 2.0 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.78 (d, 2H, J = 8.4 Hz), 7.63 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.80 (s, 1H),3.80-3.70 (m, 2H), 3.68-3.60 (m, 2H), 3.56-3.47 (m, 4H), 3.45-3.40 (m,2H), 3.26-3.16 (m, 2H), 2.80-2.60 (m, 2H), 2.44- 2.34 (m, 1H), 2.10-1.94(m, 2H), 1.80-1.68 (m, 2H), 1.66-1.50 (m, 2H), 1.48-1.32 (m, 2H), 0.90(d, 6H, J = 6.0 Hz). 707

527 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.2 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.56 (d, 2H, J = 8.4Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.51 (s, 1H),3.71-3.64 (m, 2H), 3.56-3.54 (m, 2H), 3.46-3.45 (m, 4H), 3.31-3.24 (m,2H), 2.81-2.76 (m, 1H), 2.67-2.59 (m, 4H), 2.46- 2.43 (m, 2H), 2.34-2.30(m, 1H), 1.84-1.80 (m, 2H), 1.56-1.51 (m, 2H), 0.99 (t, 6H, J = 5.6 Hz).708

529 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.13 (d, J = 1.7Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.26 (dd, J= 9.8, 7.1 Hz, 3H), 7.00 (d, J = 1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H),3.86 (qd, J = 9.8, 6.3 Hz, 2H), 3.59-3.53 (m, 4H), 3.45 (dd, J = 6.6,3.6 Hz, 4H), 2.97 (d, J = 11.3 Hz, 2H), 2.83 (p, J = 6.6 Hz, 1H),2.42-2.26 (m, 2H), 1.88-1.74 (m, 2H), 1.67 (qd, J = 12.3, 3.7 Hz, 2H),1.03 (d, J = 6.6 Hz, 6H). 709

532 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.13 (d, J = 1.6Hz, 1H), 7.89 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.24 (d, J= 8.1 Hz, 2H), 6.99 (d, J = 1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.79(tt, J = 8.1, 4.0 Hz, 1H), 3.79 (dt, J = 10.4, 4.5 Hz, 2H), 3.61 (s,4H), 3.48 (ddd, J = 11.4, 8.4, 3.4 Hz, 6H), 2.96 (d, J = 11.0 Hz, 2H),2.83 (p, J = 6.6 Hz, 1H), 2.34 (dd, J = 12.5, 10.0 Hz, 2H), 1.88 (dd, J= 12.8, 4.6 Hz, 2H), 1.83-1.75 (m, 2H), 1.68 (tt, J = 12.5, 6.3 Hz, 2H),1.56 (dtd, J = 12.6, 8.5, 4.0 Hz, 2H), 1.03 (d, J = 6.6 Hz, 6H). 710

533 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.57 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.6 Hz), 7.96- 7.88 (m, 2H), 7.76 (dd, 1H, J = 8.4, 2.4Hz), 7.20 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.00-3.90 (m,2H), 3.80-3.65 (m, 2H), 3.61-3.55 (m, 2H), 3.53-3.47 (m, 2H), 3.46- 3.40(m, 1H), 3.26-3.22 (m, 1H), 3.24 (s, 3H), 2.91 (s, 3H), 2.80-2.70 (m,1H), 2.68-2.56 (m, 4H), 2.10-1.94 (m, 3H), 1.92-1.80 (m, 2H), 0.98 (d,3H, J = 6.4 Hz), 0.80-0.70 (m, 4H). 711

533 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.30 (d, 1H, J = 1.6 Hz), 8.00- 7.90 (m, 2H), 7.78 (dd, 1H, J = 8.4, 2.0Hz), 7.21 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 4.00-3.90 (m,2H), 3.80-3.65 (m, 2H), 3.65-3.59 (m, 2H), 3.55-3.47 (m, 1H), 3.47- 3.40(m, 1H), 3.28-3.24 (m, 1H), 3.27 (s, 3H), 2.92 (s, 3H), 2.80-2.70 (m,1H), 2.68-2.55 (m, 4H), 2.10-1.95 (m, 3H), 1.94-1.80 (m, 2H), 0.98 (d,3H, J = 6.4 Hz), 0.82-0.70 (m, 4H). 712

533 1H-NMR (H NMR (400 MHz, CD3OD) δ ppm 7.98 (d, 1H, J = 2.0 Hz), 7.85(d, 1H, J = 5.6 Hz), 7.74 (d, 2H, J = 8.0 Hz), 7.47 (d, 2H, J = 8.0 Hz),6.92 (d, 1H, J = 2.0 Hz), 6.00 (d, 1H, J = 5.6 Hz), 3.95-3.90 (m, 1H),3.67-3.65 (m, 4H), 3.55-3.53 (m, 4H), 3.17-3.16 (q, 2H, J = 7.2 Hz),2.95-2.94 (m, 3H), 2.93-2.90 (m, 2H), 2.17-2.16 (m, 2H), 2.09-2.05 (m,2H), 1.21- 1.18 (m, 12H), 1.17-1.13 (t, 3H, J = 7.2 Hz). 713

534 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.30 (s, 1H), 8.20 (d, 1H, J= 1.6 Hz), 7.92 (d, 1H, J = 5.6 Hz), 7.81 (d, 2H, J = 8.4 Hz), 7.39 (d,2H, J = 8.4 Hz), 7.04 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.6 Hz),5.36-5.33 (m, 1H), 4.79 (t, 2H, J = 6.4 Hz), 4.53 (dd, 2H, J = 7.2, 5.2Hz), 3.60-3.59 (m, 4H), 3.50-3.49 (m, 4H), 2.93- 2.91 (m, 1H), 2.90 (s,3H), 2.82-2.79 (m, 2H), 2.70-2.65 (m, 2H), 2.07-1.98 (m, 4H), 1.08 (d,6H, J = 6.4 Hz). 714

534 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.6 Hz), 7.96- 7.90 (m, 2H), 7.78 (dd, 1H, J = 8.4, 2.4Hz), 7.17 (d, 1H, J = 1.6 Hz), 6.31 (d, 1H, J = 7.2 Hz), 5.99 (d, 1H, J= 5.6 Hz), 4.60-4.51 (m, 2H), 4.50-4.40 (m, 2H), 3.84-3.72 (m, 1H),3.56-3.50 (m, 4H), 3.48-3.40 (m, 4H), 2.91 (s, 3H), 2.60-2.46 (m, 3H),2.30-2.10 (m, 2H), 2.08-1.88 (m, 4H), 1.08 (d, 6H, J = 6.4 Hz). 715

534 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.5 Hz),8.27 (d, 1H, J = 2.0 Hz), 7.93 (d, 1H, J = 5.5 Hz), 7.91 (s, 1H), 7.78(dd, 1H, J = 8.5, 2.0 Hz), 7.17 (d, 1H, J = 1.5 Hz), 6.31 (d, 1H, J =7.5 Hz), 6.00 (d, 1H, J = 5.5 Hz), 3.81-3.76 (m, 1H), 3.53-3.50 (m, 4H),3.46- 3.45 (m, 4H), 3.08 (q, 2H, J = 7.0 Hz), 2.70- 2.62 (m, 1H),2.60-2.54 (m, 2H), 2.54-2.50 (m, 2H), 2.01-1.98 (m, 2H), 1.91-1.87 (m,2H), 1.09-1.04 (m, 9H), 1.01-0.99 (m, 6H). 716

534 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.69 (s, 1H), 8.27 (d, 1H, J= 1.2 Hz), 7.92 (d, 1H, J = 5.6 Hz), 7.90-7.88 (m, 2H), 7.16 (d, 1H, J =1.6 Hz), 6.31 (d, 1H, J = 7.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.80-3.75(m, 1H), 3.53-3.52 (m, 4H), 3.45-3.44 (m, 4H), 3.26-3.22 (m, 1H),3.03-2.98 (m, 2H), 2.82-2.78 (m, 1H), 2.62- 2.60 (m, 1H), 2.45-2.41 (m,2H), 1.94-1.85 (m, 1H), 1.74-1.66 (m, 2H), 1.36-1.26 (m, 1H), 1.07 (d,6H, J = 6.4 Hz), 1.04-0.99 (m, 9H). 717

534 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.68 (s, 1H), 8.26 (d, 1H, J= 1.2 Hz), 7.92 (d, 1H, J = 5.6 Hz), 7.90-7.88 (m, 2H), 7.16 (d, 1H, J =1.6 Hz), 6.31 (d, 1H, J = 7.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 3.81-3.75(m, 1H), 3.53-3.52 (m, 4H), 3.45-3.44 (m, 4H), 3.26-3.22 (m, 1H),3.03-3.0 (m, 2H), 2.81-2.78 (m, 1H), 2.62-2.59 (m, 1H), 2.45-2.40 (m,2H), 1.94-1.85 (m, 1H), 1.78-1.63 (m, 2H), 1.35-1.24 (m, 1H), 1.07 (d,6H, J = 6.4 Hz), 1.04-0.99 (m, 9H). 718

535 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.68 (d, 1H, J = 1.6 Hz),8.30 (d, 1H, J = 1.2 Hz), 8.20 (s, 1H), 7.94 (d, 1H, J = 5.6 Hz), 7.91(s, 1H), 7.85 (dd, 1H, J = 8.0, 2.4 Hz), 7.18 (d, 1H, J = 1.6 Hz), 6.00(d, 1H, J = 5.6 Hz), 5.35-5.30 (m, 1H), 4.78 (t, 2H, J = 7.2 Hz), 4.52(dd, 2H, J = 7.6, 5.6 Hz), 3.72-3.66 (m, 2H), 3.65-3.59 (m, 2H),3.51-3.50 (m, 4H), 2.98-2.95 (m, 1H), 2.94 (s, 3H), 2.90-2.84 (m, 1H),2.76-2.73 (m, 1H), 2.59-2.53 (m, 1H), 1.95-1.90 (m, 1H), 1.83-1.81 (m,1H), 1.74-1.71 (m, 1H), 1.45- 1.33 (m, 1H), 1.03 (d, 6H, J = 6.4 Hz).719

535 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.66 (d, 1H, J = 1.6 Hz),8.29 (d, 1H, J = 1.6 Hz), 8.21- 8.17 (m, 1H), 7.94 (d, 1H, J = 5.6 Hz),7.91 (s, 1H), 7.85 (dd, 1H, J = 8.0, 2.0 Hz), 7.18 (d, 1H, J = 1.6 Hz),6.0 (d, 1H, J = 5.2 Hz), 5.34- 5.30 (m, 1H), 4.78 (t, 2H, J = 7.2 Hz),4.52 (dd, 2H, J = 7.6, 5.6 Hz), 3.72-3.66 (m, 2H), 3.65-3.59 (m, 2H),3.51-3.50 (m, 4H), 2.98- 2.95 (m, 1H), 2.94 (s, 3H), 2.90-2.84 (m, 1H),2.78-2.75 (m, 1H), 2.58-2.53 (m, 1H), 1.96- 1.90 (m, 1H), 1.84-1.72 (m,2H), 1.46-1.36 (m, 1H), 1.04 (d, 6H, J = 6.4 Hz). 720

537 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.25 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.68- 7.62 (m, 2H), 7.37-7.32 (m, 1H), 7.10(s, 1H), 6.32 (d, 1H, J = 7.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 3.80-3.77(m, 1H), 3.60-3.57 (m, 4H), 3.52-3.51 (m, 4H), 2.96 (s, 3H), 2.67-2.57(m, 3H), 2.49-2.45 (m, 2H), 2.13-2.09 (m, 2H), 2.01-1.97 (m, 2H), 1.07(d, 6H, J = 6.4 Hz), 0.98 (d, 6H, J = 6.8 Hz). 721

537 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.68- 7.62 (m, 2H), 7.36 (t, 1H, J = 8.4 Hz),7.11 9d, 1H, J = 1.6 Hz), 6.33 (d, 1H, J = 7.6 Hz), 5.99 (d, 1H, J = 5.6Hz), 3.82-3.76 (m, 1H), 3.54- 3.50 (m, 4H), 3.44-3.40 (m, 4H), 2.96 (s,3H), 2.70-2.67 (m, 1H), 2.60-2.56 (m, 2H), 2.48- 2.46 (m, 2H), 2.14-2.10(m, 2H), 2.00-1.92 (m, 2H), 1.09 (d, 6H, J = 6.8 Hz), 1.00 (d, 6H, J =6.8 Hz). 722

537 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (s, 1H), 7.91 (d, 1H, J= 5.2 Hz), 7.65-7.63 (m, 2H), 7.52 (t, 1H, J = 8.4 Hz), 7.12 (s, 1H),6.33 (d, 1H, J = 7.2 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.81-3.76 (m, 1H),3.56-3.52 (m, 4H), 3.46- 3.44 (m, 4H), 2.99 (s, 3H), 2.80-2.70 (m, 3H),2.52-2.49 (m, 2H), 2.08-2.07 (m, 1H), 1.76- 1.70 (m, 2H), 1.38-1.36 (m,1H), 1.09 (d, 6H, J = 6.8 Hz), 1.10-0.90 (m, 6H). 723

537 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.26 (d, 1H, J = 1.6 Hz),8.21 (s, 1H), 7.91 (d, 1H, J = 5.2 Hz), 7.68-7.65 (m, 2H), 7.64 (s, 1H),7.54- 7.50 (m, 1H), 7.11 (s, 1H), 6.33 (d, 1H, J = 7.2 Hz), 5.99 (d, 1H,J = 5.6 Hz), 3.81-3.76 (m, 1H), 3.56-3.52 (m, 4H), 3.46-3.44 (m, 4H),3.02-2.97 (m, 1H), 2.99 (s, 3H), 2.90-2.80 (m, 1H), 2.79-2.70 (m, 1H),2.61-2.55 (m, 1H), 2.08-2.07 (m, 1H), 1.89-1.79 (m, 1H), 1.79- 1.70 (m,1H), 1.38-1.36 (m, 1H), 1.09 (d, 6H, J = 6.8 Hz), 1.10-0.90 (m, 6H). 724

537 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.88- 8.85 (m, 1H), 8.33 (d,1H, J = 1.6 Hz), 7.93 (d, 1H, J = 5,6 Hz), 7.65-7.63 (m, 2H), 7.43 (t,1H, J = 8.4 Hz), 7.15 (d, 1H, J = 1.2 Hz), 6.45-6.41 (m, 1H), 6.00 (d,1H, J = 5.6 Hz), 3.81-3.80 (m, 1H) 3.78-3.77 (m, 1H), 3.56-3.52 (m, 4H),3.46-3.44 (m, 4H), 3.30-3.27 (m, 2H), 3.25- 3.06 (m, 2H), 3.06 (s, 3H),2.50-2.49 (m, 1H), 2.39-2.36 (m, 1H), 2.13-2.12 (m, 1H), 1.98- 1.91 (m,1H), 1.29-1.26 (m, 6H), 1.09 (d, 6H, J = 6.4 Hz). 725

538 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.46 (d, 1H, J = 4.8 Hz, 1),8.18 (s, 1H), 7.98 (d, 1H, J = 5.6 Hz), 7.29 (t, 1H, J = 5.6 Hz), 7.17(s, 1H), 6.29 (d, 1H, J = 7.6 Hz), 6.03 (d, 1H, J = 5.6 Hz), 3.80-3.76(m, 1H), 3.54-3.52 (m, 4H), 3.48-3.47 (m, 4H), 3.04 (s, 3H), 2.74-2.72(m. 2H), 2.58-2.50 (m, 2H), 2.20-2.16 (m, 2H), 2.10-2.04 (m, 2H), 1.09(d, 6H, J = 6.8 Hz), 1.05 (d, 6H, J = 6.0 Hz). 726

539 1H-NMR (H-NMR (500 MHz, 4d-MeOD) δ ppm 8.00 (d, 1H, J = 1.5 Hz),7.90 (d, 1H, J = 5.5 Hz), 7.63 (d, 1H, J = 8.0 Hz), 7.41 (d, 1H, J = 1.0Hz), 7.27 (dd, 1H, J = 8.0, 1.0 Hz), 6.86 (d, 1H, J = 1.0 Hz), 6.03 (d,1H, J = 5.0 Hz), 5.43-5.41 (m, 1H), 4.92-4.90 (m, 2H), 4.68-4.66 (m,2H), 3.80-3.75 (m, 2H), 3.75-3.70 (m, 2H), 3.56- 3.52 (m, 4H), 3.37-3.32(m, 2H), 3.25-3.18 (m, 1H), 2.84-2.76 (m, 3H), 2.09-2.05 (m, 2H),1.96-1.88 (m, 2H), 1.30 (d, 6H, J = 6.5 Hz). 727

540 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4Hz), 7.09 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 4.00-3.82 (m,2H), 3.82-3.65 (m, 2H), 3.58-3.54 (m, 2H), 3.52-3.48 (m, 2H), 2.80- 2.65(m, 2H), 2.65-2.50 (m, 3H), 2.08-1.90 (m, 5H), 0.85 (d, 6H, J = 6.4 Hz),0.84-.074 (m, 4H). 728

541 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.78 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 3.74-3.68 (m,2H), 3.68-3.62 (m, 1H), 3.58-3.50 (m, 2H), 3.48-3.40 (m, 4H), 3.30- 3.20(m, 1H), 2.88 (s, 3H), 2.74-2.70 (m, 1H), 2.68-2.56 (m, 4H), 2.54-2.50(m, 2H), 2.47- 2.40 (m, 2H), 2.03-1.92 (m, 2H), 1.90-1.78 (m, 2H), 0.99(d, 6H, J = 6.4 Hz). 729

541 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (s, 1H), 7.92 (d, 1H, J= 5.2 Hz), 7.85 (d, 2H, J = 7.2 Hz), 8.46 (d, 2H, J = 7.2 Hz), 7.07 (s,1H), 5.99 (d, 1H, J = 5.2 Hz), 3.78-3.74 (m, 2H), 3.70-3.65 (m, 2H),3.52-3.43 (m, 1H), 3.52- 3.48 (m, 2H), 3.47-3.44 (m, 2H), 3.30-3.21 (m,2H), 2.96 (s, 3H), 2.75-2.70 (m, 2H), 2.35-2.30 (m, 2H), 2.10-2.01 (m,2H), 1.75-1.71 (m, 2H), 1.62-1.57 (m, 2H), 1.43-1.39 (m, 2H), 1.01- 0.80(m, 6H). 730

541 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.0 Hz),7.90 (d, 1H, J = 5.5 Hz), 7.77 (d, 2H, J = 8.0 Hz), 7.48 (d, 2H, J = 8.0Hz), 7.03 (d, 1H, J = 1.5 Hz), 5.98 (d, 1H, J = 5.5 Hz), 3.71-3.68 (m,2H), 3.68-3.65 (m, 1H), 3.55-3.53 (m, 2H), 3.47-3.43 (m, 4H), 3.30- 3.25(m, 2H), 2.91 (s, 3H), 2.81-2.77 (m, 2H), 2.71-2.68 (m, 1H), 2.65-2.60(m, 2H), 2.54- 2.51 (m, 2H), 2.39-2.36 (m, 1H), 1.80-1.78 (m, 2H),1.72-1.69 (m, 1H), 1.40-1.35 (m, 1H), 1.01 (t, 6H, J = 6.0 Hz). 731

542 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.5 Hz),8.29 (d, 1H, J = 1.5 Hz), 7.94- 7.91 (m, 2H), 7.77 (dd, 1H, J = 8.5, 2.0Hz), 7.19 (d, 1H, J = 1.5 Hz), 5.98 (d, 1H, J = 5.0 Hz), 3.71-3.66 (m,2H), 3.65-3.63 (m, 1H), 3.56- 3.55 (m, 2H), 3.48-3.46 (m, 4H), 3.30-3.25(m, 1H), 2.92 (s, 3H), 2.72-2.69 (m, 1H), 2.63-2.60 (m, 4H), 2.52-2.47(m, 4H), 2.02-2.00 (m, 2H), 1.92-1.86 (m, 2H), 1.00 (d, 6H, J = 6.5 Hz).732

545 733

549 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.5 Hz), 7.95- 7.93 (m, 2H), 7.79 (dd, 1H, J = 8.5, 2.5Hz), 7.19 (d, 1H, J = 1.5 Hz), 6.01 (d, 1H, J = 5.5 Hz), 5.34 (quintet,1H, J = 6.0 Hz), 4.79 (t, 2H, J = 7.0 Hz), 4.56-4.52 (m, 4H), 4.45 (t,2H, J = 6.0 Hz), 3.72-3.68 (m, 2H), 3.63-3.59 (m, 2H), 3.52-3.50 (m,4H), 3.45-3.43 (m, 1H), 2.92 (s, 3H), 2.54-2.52 (m, 2H), 2.19-2.15 (m,2H), 2.04-1.98 (m, 2H), 1.95-1.91 (m, 2H). 734

549 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.5 Hz),8.29 (d, 1H, J = 2.0 Hz), 7.95- 7.92 (m, 2H), 7.79 (dd, 1H, J = 8.5, 2.0Hz), 7.19 (d, 1H, J = 2.0 Hz), 6.01 (d, 1H, J = 5.5 Hz), 5.35 (quintet,1H, J = 5.5 Hz), 4.80 (t, 2H, J = 6.5 Hz), 4.54 (dd, 2H, J = 7.5, 5.5Hz), 3.71-3.70 (m, 2H), 3.67-3.60 (m, 2H), 3.52- 3.51 (m, 4H), 3.33-3.30(m, 1H), 3.09 (q, 2H, J = 6.5 Hz), 2.70-2.55 (m, 2H), 2.55-2.50 (m, 2H),2.02-1.98 (m, 2H), 1.09 (t, 3H, J = 6.5 Hz), 1.01 (d, 6H, J = 6.5 Hz).735

550 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.57 (d, 1H, J = 1.6 Hz),8.27 (d, 1H, J = 1.2 Hz), 7.96- 7.88 (m, 2H), 7.78 (dd, 1H, J = 8.0, 2.0Hz), 7.17 (d, 1H, J = 1.6 Hz), 6.30 (d, 1H, J = 7.6 Hz), 5.99 (d, 1H, J= 5.6 Hz), 3.80-3.70 (m, 1H), 3.60-3.50 (m, 4H), 3.48-3.42 (m, 4H),3.44-3.41 (m, 1H), 3.26-3.20 (m, 1H), 3.25 (s, 3H), 2.91 (s, 3H),2.80-2.70 (m, 1H), 2.67-2.55 (m, 4H), 2.05-1.95 (m, 2H), 1.92-1.80 (m,2H), 1.08 (d, 6H, J = 6.8 Hz), 0.98 (d, 3H, j = 7.2 Hz). 736

550 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.6 Hz), 8.00- 7.90 (m, 2H), 7.77 (dd, 1H, J = 8.0, 2.0Hz), 7.18 (d, 1H, J = 1.6 Hz), 6.32 (d, 1H, J = 7.6 Hz), 6.00 (d, 1H, J= 5.2 Hz), 3.90-3.70 (m, 1H), 3.60-3.50 (m, 4H), 3.47-3.42 (m, 4H),3.43-3.40 (m, 1H), 3.30-3.20 (m, 1H), 3.25 (s, 3H), 2.92 (s, 3H),2.80-2.72 (m, 1H), 2.70-2.58 (m, 4H), 2.40-1.96 (m, 2H), 1.94-1.80 (m,2H), 1.09 (d, 6H, J = 6.8 Hz), 0.99 (d, 3H, J = 6.8 Hz). 737

552 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.04 (t, J = 2.2 Hz, 1H),7.97-7.81 (m, 2H), 7.26-7.16 (m, 2H), 7.01 (d, J = 1.8 Hz, 1H), 5.98 (d,J = 5.5 Hz, 1H), 5.33-5.23 (m, 1H), 4.74 (t, J = 6.9 Hz, 2H), 4.48 (dd,J = 7.6, 5.1 Hz, 2H), 3.65 (br.s, 2H), 3.55 (br.s, 2H), 3.45 (dd, J =6.7, 3.7 Hz, 4H), 3.29 (s, 5H), 2.87 (s, 3H), 2.72-2.50 (m, 3H), 1.93(d, J = 13.0 Hz, 2H), 1.82 (d, J = 13.1 Hz, 2H), 0.95 (d, J = 6.5 Hz,6H). 738

557 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.22 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4Hz), 7.06 (d, 1H, J = 1.6 Hz), 6.32 (d, 1H, J = 7.6 Hz), 6.00 (d, 1H, mJ= 5.2 Hz), 3.850-3.75 (m, 1H), 3.55-3.50 (m, 4H), 3.47-3.42 (m, 4H),2.80-2.65 (m, 2H), 2.65-2.50 (m, 3H), 2.08- 1.90 (m, 4H), 1.08 (d, 6H, J= 6.4 Hz), 0.85 (d, 6H, J = 6.4 Hz). 739

557 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.2 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.04 (s, 1H), 5.97 (d, 1H, J = 5.6 Hz), 4.23- 4.2.2 (m, 1H),3.69-3.65 (m, 2H), 3.65-3.63 (m, 1H), 3.55-3.54 (m, 2H), 3.52-3.50 (m,1H), 3.49-3.45 (m, 4H), 3.30-3.26 (m, 3H), 2.89 (s, 3H), 2.74-2.66 (m,2H), 2.65-2.50 (m, 6H), 1.98-1.93 (m, 2H), 1.92-1.88 (m, 2H), 0.95 (d,3H, J = 6.4 Hz). 740

557 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.5 Hz),7.91 (d, 1H, J = 5.5 Hz), 7.79 (d, 2H, J = 8.5 Hz), 7.39 (d, 2H, J = 8.5Hz), 7.04 (d, 1H, J = 1.5 Hz), 5.97 (d, 1H, J = 5.5 Hz), 4.30-4.20 (m,1H), 3.69-3.65 (m, 2H), 3.65-3.61 (m, 1H), 3.55-3.54 (m, 2H), 3.51- 3.48(m, 1H), 3.49-3.45 (m, 4H), 3.30-3.26 (m, 3H), 2.89 (s, 3H), 2.69-2.65(m, 2H), 2.65-2.50 (m, 6H), 1.98-1.95 (m, 2H), 1.90-1.88 (m, 2H), 0.95(d, 3H, J = 6.5 Hz). 741

558 1H-NMR (H NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.5 Hz),8.30 (d, 1H, J = 1.5 Hz), 7.95- 7.91 (m, 2H), 7.80-7.78 (m, 1H), 7.19(d, 1H, J = 1.5 Hz), 5.99 (d, 1H, J = 5.0 Hz), 4.23-4.21 (m, 1H),3.74-3.69 (m, 2H), 3.70-3.65 (m, 1H), 3.56-3.55 (m, 2H), 3.49-3.47 (m,5H), 3.31- 3.29 (m, 3H), 2.93 (s, 3H), 2.65-2.64 (m, 1H), 2.64-2.60 (m,6H), 2.51-2.50 (m, 1H), 2.05- 2.01 (m, 2H), 1.99-1.98 (m, 2H), 0.96-0.95(d, 3H, J = 6.5 Hz). 742

558 1H-NMR (H NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.30 (d, 1H, J = 2.0 Hz), 7.96- 7.93 (m, 2H), 7.79 (dd, 1H, J = 8.0, 2.0Hz), 7.19 (d, 1H, J = 1.5 Hz), 5.99 (d, 1H, J = 5.5 Hz), 3.73-3.68 (m,2H), 3.69-3.65 (m, 1H), 3.67-3.56 (m, 2H), 3.55-3.49 (m, 4H), 3.31- 3.28(m, 4H), 2.94 (s, 3H), 2.95-2.85 (m, 2H), 2.66-2.65 (m, 2H), 2.56-2.53(m, 2H), 2.49- 2.48 (m, 2H), 2.18-1.99 (m, 4H), 1.04-1.03 (m, 3H). 743

565 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.57 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.6 Hz), 7.95- 7.90 (m, 2H), 7.77 (dd, 1H, J = 8.0 Hz,2.0 Hz), 7.18 (d, 1H, J = 1.6 Hz), 6.01 (d, 1H, J = 5.2 Hz), 5.39-5.28(m, 1H), 4.79 (t, 2H, J = 7.2 Hz), 4.53 (dd, 2H, J = 7.2, 5.2 Hz),3.80-3.75 (m, 2H), 3.72-3.67 (m, 2H), 3.63-3.58 (m, 4H), 3.53-3.49 (m,1H), 3.32-3.20 (m, 1H), 3.26 (s, 3H), 2.91 (s, 3H), 2.80-3.75 (m, 1H),2.70-2.56 (m, 4H), 2.05-1.98 (m, 2H), 1.95-1.79 (m, 2H), 0.98 (d, 3H, J= 6.8 Hz). 744

565 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.57 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.6 Hz), 7.95- 7.90 (m, 2H), 7.77 (dd, 1H, J = 8.0 Hz,2.0 Hz), 7.18 (d, 1H, J = 1.6 Hz), 6.01 (d, 1H, J = 5.2 Hz), 5.39-5.28(m, 1H), 4.79 (t, 2H, J = 7.2 Hz), 4.53 (dd, 2H, J = 7.2, 5.2 Hz),3.80-3.75 (m, 2H), 3.72-3.67 (m, 2H), 3.63-3.58 (m, 4H), 3.53-3.49 (m,1H), 3.32-3.20 (m, 1H), 3.26 (s, 3H), 2.91 (s, 3H), 2.80-3.75 (m, 1H),2.70-2.56 (m, 4H), 2.05-1.98 (m, 2H), 1.95-1.79 (m, 2H), 0.98 (d, 3H, J= 6.8 Hz). 745

571 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.5 Hz),7.90 (d, 1H, J = 5.5 Hz), 7.78 (d, 2H, J = 8.5 Hz), 7.38 (d, 2H, J = 8.5Hz), 7.03 (d, 1H, J = 1.0 Hz), 5.96 (d, 1H, J = 5.5 Hz), 3.70-3.65 (m,2H), 3.65-3.58 (m, 1H), 3.55-3.51 (m, 2H), 3.46-3.41 (m, 6H), 3.30- 3.22(m, 2H), 3.24 (s, 3H), 2.87 (s, 3H), 2.77- 2.73 (m, 1H), 2.65-2.58 (m,6H), 2.50-2.47 (m, 1H), 1.97-1.94 (m, 2H), 1.86-1.82 (m, 2H), 1.00 (d,3H, J = 6.0 Hz). 746

571 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.5 Hz),7.90 (d, 1H, J = 5.5 Hz), 7.78 (d, 2H, J = 8.5 Hz), 7.38 (d, 2H, J = 8.5Hz), 7.03 (d, 1H, J = 1.0 Hz), 5.96 (d, 1H, J = 5.5 Hz), 3.70-3.65 (m,2H), 3.65-3.58 (m, 1H), 3.55-3.51 (m, 2H), 3.46-3.41 (m, 6H), 3.30- 3.22(m, 2H), 3.24 (s, 3H), 2.87 (s, 3H), 2.77- 2.73 (m, 1H), 2.65-2.58 (m,6H), 2.50-2.47 (m, 1H), 1.97-1.94 (m, 2H), 1.86-1.82 (m, 2H), 1.00 (d,3H, J = 6.0 Hz). 747

572 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (d, 1H, J = 1.6 Hz),7.93 (d, 1H, J = 5.6 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4Hz), 7.06 (d, 1H, J = 2.0 Hz), 6.01 (d, 1H, J = 5.6 Hz), 5.34 (quintet,1H, J = 5.6 Hz), 4.79 (t, 2H, J = 7.2 Hz), 4.53 (dd, 2H, J = 8.0, 5.6Hz), 3.80-3.75 (m, 2H), 3.70-3.65 (m, 2H), 3.55- 3.45 (m, 4H), 2.78-2.70(m, 2H), 2.65-2.50 (m, 3H), 2.08-1.80 (m, 4H), 0.85 (d, 6H, J = 6.4 Hz).748

572 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.57 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 2.0 Hz), 7.95- 7.90 (m, 2H), 7.77 (dd, 1H, J = 8.0, 2.0Hz), 7.18 (d, 1H, J = 1.2 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.73-3.67 (m,2H), 3.58-3.53 (m, 2H), 3.49-3.40 (m, 4H), 3.40-3.35 (m, 2H), 3.32- 3.20(m, 4H), 3.25 (s, 3H), 2.92 (s, 3H), 2.81- 2.75 (m, 2H), 2.60-2.52 (m,4H), 2.50-2.47 (m, 1H), 2.03-1.95 (m, 2H), 1.90-1.84 (m, 2H), 0.99 (d,3H, J = 6.8 Hz). 749

572 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.57 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 2.0 Hz), 7.95- 7.90 (m, 2H), 7.77 (dd, 1H, J = 8.0, 2.0Hz), 7.18 (d, 1H, J = 1.2 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.73-3.67 (m,2H), 3.58-3.53 (m, 2H), 3.49-3.40 (m, 4H), 3.40-3.35 (m, 2H), 3.32- 3.20(m, 4H), 3.25 (s, 3H), 2.92 (s, 3H), 2.81- 2.75 (m, 2H), 2.60-2.52 (m,4H), 2.50-2.47 (m, 1H), 2.03-1.95 (m, 2H), 1.90-1.84 (m, 2H), 0.99 (d,3H, J = 6.8 Hz). 750

586 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.5 Hz),8.28 (d, 1H, J = 1.0 Hz), 7.93- 7.92 (m, 2H), 7.78 (dd, 1H, J = 7.0, 2.0Hz), 7.18 (s, 1H), 6.69 (d, 1H, J = 76.0 Hz), 6.31 (d, 1H, J = 7.5 Hz),6.00 (d, 1H, J = 5.0 Hz), 3.94- 3.89 (m, 1H), 3.84-3.75 (m, 1),3.55-3.52 (m, 4H), 3.48-3.45 (m, 4H), 2.93 (s, 3H), 2.87-2.81 (m, 1H),2.70-2.61 (m, 4H), 2.06-2.00 (m, 2H), 1.95-1.86 (m, 2H), 1.09 (d, 6H, J= 6.5 Hz), 1.02 (d, 3H, J = 6.5 Hz). 751

407 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H), 7.98 (d, J =1.8 Hz, 1H), 7.85 (d, J = 5.5 Hz, 1H), 7.81-7.70 (m, 2H), 7.55-7.38 (m,2H), 6.94 (d, J = 1.8 Hz, 1H), 6.00 (d, J = 5.5 Hz, 1H), 4.86 (d, J =3.6 Hz, 1H), 4.03 (s, 2H), 3.85 (s, 2H), 3.62 (s, 2H), 3.59-3.47 (m,3H), 3.16-3.07 (m, 1H), 3.00 (dd, J = 12.8, 9.3 Hz, 1H), 2.09-1.96 (m,1H), 0.92 (dt, J = 4.8, 2.8 Hz, 2H), 0.86 (ddt, J = 7.5, 4.6, 2.5 Hz,2H). 752

407 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.95 (d, J = 1.8 Hz, 1H),7.83 (d, J = 5.4 Hz, 1H), 7.79- 7.66 (m, 2H), 7.44-7.35 (m, 2H), 6.92(d, J = 1.8 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 5.48 (s, 1H), 4.02 (s,2H), 3.97 (dd, J = 8.0, 4.7 Hz, 1H), 3.84 (s, 2H), 3.71 (dd, J = 10.9,4.7 Hz, 1H), 3.63 (s, 2H), 3.60-3.55 (m, 1H), 3.54 (d, J = 8.0 Hz, 2H),2.01 (tt, J = 8.0, 4.7 Hz, 1H), 0.92 (dt, J = 4.8, 2.8 Hz, 2H), 0.85(ddt, J = 7.4, 4.6, 2.5 Hz, 2H). 753

407 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.5 Hz, 1H), 7.77- 7.63 (m, 2H), 7.48-7.35 (m, 2H), 6.92(d, J = 1.8 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 4.03 (s, 2H), 3.98 (dd, J= 8.0, 4.7 Hz, 1H), 3.85 (s, 2H), 3.72 (dd, J = 210.9, 4.8 Hz, 1H), 3.63(s, 2H), 3.58 (dd, J = 10.8, 8.0 Hz, 1H), 3.54 (s, 2H), 2./02 (tt, J =7.9, 4.7 Hz, 1H), 0.92 (dt, J = 4.8, 2.8 Hz, 2H), 0.86 (ddt, J = 7.5,4.6, 2.5 Hz, 2H). 754

411 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.05 (d, J = 1.8 Hz, 1H),7.89 (d, J = 5.4 Hz, 1H), 7.84- 7.69 (m, 2H), 7.51-7.33 (m, 2H), 6.96(d, J = 1.8 Hz, 1H), 6.04 (d, J = 5.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H),4.02 (dd, J = 7.9, 4.7 Hz, 1H), 3.80-3.68 (m, 5H), 3.63-3.48 (m, 5H),2.63 (p, J = 1.9 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 755

419 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 1.8 Hz, 1H), 7.89(d, J = 5.4 Hz, 1H), 7.86- 7.77 (m, 2H), 7.63-7.53 (m, 2H), 7.05 (d, J =1.8 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 4.72 (d, J = 6.1 Hz, 2H), 4.65(d, J = 6.0 Hz, 2H), 3.91 (s, 2H), 3.70 (s, 2H), 3.51 (d, J = 27.0 Hz,5H), 2.01 (tt, J = 7.7, 4.9 Hz, 1H), 0.81-0.65 (m, 4H). 756

421 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.97 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.4 Hz, 1H), 7.74- 7.66 (m, 2H), 7.42-7.35 (m, 2H),7.36-7.21 (m, 1H), 6.93 (d, J = 1.8 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H),4.04 (d, J = 9.6 Hz, 2H), 3.91- 3.85 (m, 0H), 3.83-3.72 (m, 7H),3.69-3.61 (m, 6H), 3.55 (d, J = 6.9 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H),2.72 (dt, J = 11.3, 5.6 Hz, 5H), 2.02 (tt, J = 7.8, 4.7 Hz, 1H), 0.92(dt, J = 4.8, 2.8 Hz, 2H), 0.86 (ddt, J = 7.5, 4.6, 2.6 Hz, 2H). 757

421 758

421 759

425 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.02 (dd, J = 2.8, 1.8 Hz,1H), 7.86 (d, J = 5.4 Hz, 1H), 7.81 (t, J = 8.2 Hz, 1H), 7.30-7.15 (m,2H), 7.04-6.95 (m, 1H), 6.00 (d, J = 5.5 Hz, 1H), 4.10-3.94 (m, 3H),3.85 (s, 2H), 3.72 (dd, J = 10.9, 4.9 Hz, 1H), 3.68-3.48 (m, 5H), 2.02(tt, J = 7.9, 4.8 Hz, 1H), 0.92 (dt, J = 4.9, 2.8 Hz, 2H), 0.86 (ddt, J= 7.5, 4.7, 2.5 Hz, 2H). 760

433 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 1.i8 Hz, 1H),7.84 (d, J = 5.4 Hz, 1H), 7.73- 7.63 (m, 2H), 7.41-7.32 (m, 2H), 6.93(d, J = 1.8 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 4.70 (t, J = 6.8 Hz, 2H),4.44 (t, J = 6.4 Hz, 2H), 4.08- 3.98 (m, 3H), 3.85 (s, 2H), 3.71 (s,2H), 3.63 (s, 2H), 3.54 (s, 2H), 2.02 (tt, J = 7.9, 4.8 Hz, 1H), 0.92(dt, J = 4.8, 2.8 Hz, 2H), 0.86 (ddt, J = 7.5, 4.6, 2.5 Hz, 2H). 761

435 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.4 Hz, 1H), 7.73- 7.65 (m, 2H), 7.42-7.36 (m, 2H), 6.92(d, J = 1.8 Hz, 1H), 5.98 (d, J = 5.5 Hz, 1H), 4.02 (s, 2H), 3.84 (s,2H), 3.79 (s, 1H), 3.62 (s, 2H), 3.59-3.47 (m, 2H), 3.34 (s, 6H), 2.01(tt, J = 7.9, 4.7 Hz, 1H), 1.20 (s, 3H), 1.12 (s, 3H), 0.96-0.90 (m,2H), 0.86 (tdd, J = 7.5, 5.3, 2.4 Hz, 2H), 762

439 1H-NMR (H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.5 Hz, 1H), 7.75- 7.67 (m, 2H), 7.43-7.34 (m, 2H), 6.89(d, J = 1.9 Hz, 1H), 6.00 (d, J = 5.5 Hz, 1H), 5.41 (tt, J = 6.2, 5.1Hz, 1H), 4.89 (ddd, J = 7.4, 6.2, 1.0 Hz, 2H), 4.65 (ddd, J = 7.5, 5.2,0.9 Hz, 2H), 3.97 (dd, J = 8.0, 4.7 Hz, 1H), 3.74-3.68 (m, 3H), 3.57(dd, J = 10.8, 8.0 Hz, 1H), 3.53 (dd, J = 6.5, 3.9 Hz, 4H). 763

439 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.4 Hz, 1H), 7.77- 7.62 (m, 2H), 7.47-7.33 (m, 2H), 6.89(d, J = 1.8 Hz, 1H), 6.01 (d, J = 5.5 Hz, 1H), 5.41 (tt, J = 6.3, 5.1Hz, 1H), 4.90 (ddd, J = 7.4, 6.2, 1.0 Hz, 2H), 4.66 (ddd, J = 7.5, 5.1,0.9 Hz, 2H), 3.99 (dd, J = 7.9, 4.7 Hz, 1H), 3.80 (s, 3H), 3.77-3.64 (m,2H), 3.59 (dd, J = 10.9, 8.0 Hz, 1H), 3.54-3.44 (m, 4H). 764

439 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.95 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.5 Hz, 1H), 7.76- 7.59 (m, 2H), 7.49-7.32 (m, 2H), 6.89(d, J = 1.8 Hz, 1H), 6.00 (d, J = 5.5 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H),3.79 (s, 1H), 3.72 (d, J = 6.1 Hz, 4H), 3.57-3.41 (m, 4H), 1.29 (t, J =7.1 Hz, 3H), 1.20 (s, 3H), 1.12 (s, 3H). 765

440 766

443 1H-NMR (H NMR (500 MHz, Methanol-d4) δ 7.98 (dd, J = 12.3, 1.8 Hz,1H), 7.86 (d, J = 5.4 Hz, 1H), 7.69 (dd, J = 16.3, 7.9 Hz, 2H), 7.25 (t,J = 7.2 Hz, 2H), 6.94 (dd, J = 10.9, 1.8 Hz, 1H), 6.42 (s, 0H), 6.02 (d,J = 5.4 Hz, 1H), 5.57 (s, 1H), 4.07 (d, J = 18.4 Hz, 2H), 3.87 (s, 2H),3.65 (s, 2H), 3.57 (s, 2H), 3.48 (s, 1H), 3.38 (s, 2H), 3.05 (dt, J =18.3, 6.0 Hz, 2H), 2.94 (t, J = 5.8 Hz, 1H), 2.61 (t, J = 5.9 Hz, 1H),2.46 (t, J = 5.9 Hz, 1H), 2.15 (s, 1H), 2.04 (tt, J = 8.2, 5.0 Hz, 1H),0.95 (dt, J = 5.5, 3.1 Hz, 2H), 0.88 (dq, J = 10.4, 4.0, 3.6 Hz, 2H).767

443 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.94 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.5 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.0 Hz,2H), 6.90 (d, J = 1.9 Hz, 1H), 6.00 (d, J = 5.5 Hz, 1H), 4.25 (s, 3H),4.03 (s, 3H), 3.84 (s, 2H), 3.58 (d, J = 26.6 Hz, 5H), 2.75-2.66 (m,2H), 2.42 (td, J = 9.7, 2.9 Hz, 2H), 2.06-1.99 (m, 1H), 1.30 (d, J =14.4 Hz, 1H), 0.99-0.81 (m, 4H). 768

447 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 1.8 Hz, 1H), 7.88(d, J = 5.4 Hz, 1H), 7.78- 7.68 (m, 2H), 7.56-7.47 (m, 2H), 7.02 (d, J =1.9 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 3.91 (s, 2H), 3.86 (td, J = 11.2,2.3 Hz, 2H), 3.69 (s, 2H), 3.62 (dt, J = 11.1, 3.8 Hz, 2H), 3.50 (d, J =25.8 Hz, 4H), 2.07-1.91 (m, 3H), 1.53 (d, J = 13.1 Hz, 2H), 0.84-0.67(m, 4H). 769

447 770

449 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 2H), 7.98 (d, J =1.8 Hz, 1H), 7.85 (d, J = 5.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.43(d, J = 8.0 Hz, 2H), 6.94 (d, J = 1.8 Hz, 1H), 6.00 (d, J = 5.5 Hz, 1H),4.55 (s, 1H), 4.03 (s, 3H), 3.82 (d, J = 23.8 Hz, 2H), 3.79-3.67 (m,1H), 3.63 (s, 2H), 3.53 (d, J = 18.9 Hz, 2H), 2.05- 1.94 (m, 1H), 1.28(s, 1H), 1.16 (dd, J = 16.5, 9.4 Hz, 6H), 0.96-0.81 (m, 5H). 771

453 1H-NMR (H NMR (500 MHz, Methanol-d4) δ 8.45 (s, 2H), 8.11-7.96 (m,1H), 7.87 (dd, J = 17.6, 6.7 Hz, 3H), 7.51 (d, J = 8.2 Hz, 2H), 6.96 (d,J = 1.9 Hz, 1H), 6.05 (d, J = 5.5 Hz, 1H), 5.44 (p, J = 5.6 Hz, 1H),4.93 (t, J = 6.9 Hz, 2H), 4.68 (dd, J = 7.6, 5.1 Hz, 2H), 3.96-3.66 (m,6H), 3.56 (t, J = 5.1 Hz, 4H), 3.01 (s, 2H), 2.88 (s, 1H), 1.74 (s, 3H).772

561 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 0H), 8.14 (d, J = 2.0Hz, 1H), 7.89 (d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.33 (d, J= 8.2 Hz, 2H), 7.01 (d, J = 1.9 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.13(s, 2H), 3.92 (s, 2H), 3.70 (s, 2H), 3.57 (d, J = 25.1 Hz, 3H), 3.46 (s,1H), 3.15 (s, 4H), 2.79 (d, J = 10.7 Hz, 1H), 2.07- 1.98 (m, 1H),1.94-1.80 (m, 2H), 1.63 (d, J = 10.9 Hz, 1H), 1.51 (s, 1H), 1.22 (s,1H), 0.75 (tt, J = 7.9, 2.9 Hz, 4H). 773

462 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.16 (s, 1H), 7.91 (d, 1H, J= 5.5 Hz), 7.74 (d, 2H, J = 8.0 Hz), 7.25 (d, 2H, J = 8.0 Hz), 7.01 (s,1H), 5.99 (d, 1H, J = 5.5 Hz), 5.34 (quintet, 1H, d, 1H, J = 5.5 Hz),4.80 (t, 2H, d, 1H, J = 7.0 Hz), 4.53 (dd, 2H, d, 1H, J = 7.0, 5.5 Hz),3.72-3.67 (m, 2H), 3.63-3.58 (m, 2H), 3.55-3.45 (m, 4H), 3.20-3.15 (m,1H), 3.06-3.02 (m, 2H), 2.64- 2.59 (m, 2H), 1.75-1.70 (m, 2H), 1.57-1.52(m, 2H). 774

462 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.2 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.24 (d, 2H, J = 8.4Hz), 7.00 (s, 1H), 6.00 (d, 1H, J = 5.6 Hz), 5.34 (quintet, 1H, J = 5.2Hz), 4.79 (t, 2H, J = 7.2 Hz), 4.53 (dd, 2H, J = 7.2, 5.2 Hz), 3.69 (m,2H), 3.59 (m, 2H), 3.49-3.48 (m, 4H), 2.96- 2.93 (m, 2H), 2.60-2.52 (m,2H), 2.47 (m, 1H), 1.89-1.87 (m, 1H), 1.70-1.65 (m, 1H), 1.62- 1.58 (m,1H), 1.55-1.40 (m, 2H). 775

463 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.27 (s, 1H), 8.08 (d, 1H, J= 1.5 Hz), 7.88 (d, 1H, J = 5.5 Hz), 7.67 (d, 2H, J = 9.0 Hz), 6.97 (d,2H, J = 9.0 Hz), 6.93 (d, 1H, J = 1.5 Hz), 5.98 (d, 1H, J = 5.5 Hz),5.33 (quintet, 1H, J = 5.0 Hz), 4.79 (t, 2H, J = 7.0 Hz), 4.53 (dd, 2H,J = 7.5, 5.0 Hz), 3.70-3.68 (m, 2H), 3.65-3.64 (m, 2H), 3.48-3.46 (m,4H), 3.18-3.16 (m, 4H), 2.99- 2.97 (m, 4H). 776

464 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.28 (d, 1J, J = 2.4 Hz),8.15 (d, 1H, J = 1.2 Hz), 7.90 (d, 1H, J = 5.6 Hz), 7.70 (d, 1H, J = 8.8Hz), 7.73 (dd, 1H, J = 8.8, 2.4 Hz), 7.06 (d, 1H, J = 1.2 Hz), 5.98 (d,1H, J = 5.6 Hz), 5.33 (quintet, 1H, J = 5.6 Hz), 4.78 (t, 2H, J = 7.2Hz), 4.52 (dd, 2H, J = 7.2, 5.6 Hz), 3.70-3.65 (m, 2H), 3.65-3.58 (m,2H), 3.51-3.45 (m, 4H), 3.25- 3.15 (m, 4H), 3.05-2.93 (m, 4H). 777

464 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.09 (q, 2H, J= 7.2 Hz), 3.62-3.60 (m, 4H), 3.47-3.46 (m, 4H), 2.96-2.87 (m, 5H),2.70-2.67 (m, 1H), 2.49-2.46 (m, 1H), 2.11- 2.07 (m, 1H), 1.98-1.92 (m,1H), 1.69-1.59 (m, 1H), 1.46-1.42 (m, 1H), 1.22 (t, 3H, J = 7.2 Hz), 778

465 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.61 (s, 1H), 8.32 (d, 1H, J= 1.5 Hz), 8.29 (s, 1H), 7.99 (d, 1H, J =8.0 Hz), 7.95 (d, 1H, J 5.0Hz), 7.82 (d, 1H, J = 7.5 Hz), 7.20 (d, 1H, J = 1.5 Hz), 6.01 (d, 1H, J= 5.5 Hz), 4.10 (q, 2H, J = 7.0 Hz), 3.70-3.58 (m, 4H), 3.54-3.46 (m,4H), 3.38-3.25 (m, 1H), 3.15-3.05 (m, 2H), 3.02 (s, 3H), 2.90-2.76 (m,1H), 2.26-2.18 (m, 1H), 2.14-2.04 (m, 1H), 1.90-1.78 (m, 1H), 1.76-1.66(m, 1H), 1.23 (t, 3H, J = 7.0 Hz). 779

467 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.4 Hz, 1H), 7.73- 7.62 (m, 2H), 7.43-7.36 (m, 2H), 6.90(d, J = 1.9 Hz, 1H), 6.01 (d, J = 5.5 Hz, 1H), 5.41 (tt, J = 6.2, 5.1Hz, 1H), 4.90 (ddd, J = 7.4, 6.2, 1.0 Hz, 2H), 4.66 (ddd, J = 7.5, 5.1,0.9 Hz, 2H), 3.76 (d, J = 26.0 Hz, 1H), 3.58-3.47 (m, 4H), 1.16 (d, J =29.4 Hz, 6H). 780

467 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.97 (d, J = 1.8 Hz, 1H),7.85 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.2 Hz,2H), 6.90 (d, J = 1.8 Hz, 1H), 6.01 (d, J = 5.4 Hz, 1H), 5.46-5.35 (m,1H), 4.90 (dd, J = 7.5, 6.5 Hz, 2H), 4.66 (dd, J = 7.8, 5.2 Hz, 2H),3.88- 3.61 (m, 8H), 3.61-3.46 (m, 5H), 2.58 (q, J = 7.0 Hz, 2H), 1.29(s, 2H), 1.13 (t, J = 7.2 Hz, 3H). 781

475 782

478 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.78 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 4.09 (q, 2H, J= 7.2 Hz), 3.62-3.61 (m, 4H), 3.47-3.46 (m, 4H), 3.19-3.15 (m, 1H),3.08-3.04 (m, 1H), 2.90-2.87 (m, 2H), 2.68- 2.65 (m, 1H), 2.51-2.50 (m,1H), 2.05-2.04 (m, 1H), 1.97-1.96 (m, 1H), 1.62-1.60 (m, 1H), 1.41-1.39(m, 1H), 1.22 (t, 3H, J = 7.2 Hz), 1.09 (t, 3H, J = 6.4 Hz). 783

478 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.40 (d, 2H, J = 8.4Hz), 7.02 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 4.09 (q, 2H, J= 7.2 Hz), 3.62-3.55 (m, 4H), 3.20-3.45 (m, 4H), 3.20-3.15 (m, 1H),3.08-3.03 (m, 1H), 2.95-2.88 (m, 2H), 2.73- 2.68 (m, 1H), 2.54-2.50 (m,1H), 2.08-2.04 (m, 1H), 2.00-1.95 (m, 1H), 1.69-1.64 (m, 1H), 1.48-1.43(m, 1H), 1.22 (t, 3H, J = 7.2 Hz), 1.11 (t, 3H, J = 7.2 Hz). 784

478 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (s, 1H), 8.29 (d, 1H, J= 1.6 Hz), 8.27 (s, 1H), 7.97 (d, 1H, J = 8.0 Hz), 7.93 (d, 1H, J = 5.2Hz), 7.80 (d, 1H, J = 7.6 Hz), 7.18 (d, 1H, J = 1.2 Hz), 6.32 (d, 1H, J= 7.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 3.75-3.60 (m, 1H), 3.67-3.48 (m,4H), 3.47-3.40 (m, 4H), 3.30-3.20 (m, 1H), 3.12-3.02 (m, 2H), 3.00 (s,3H), 2.84-266 (m, 1H), 2.24-2.14 (m, 1H), 2.12-2.00 (m, 1H), 1.86-1.72(m, 1H), 1.70-1.60 (m, 1H), 1.07 (d, 6H, J = 6.4 Hz). 785

478 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.56 (d, 1H, J = 1.6 Hz),8.27 (d, 1H, J = 1.6 Hz), 7.96- 7.90 (m, 2H), 7.75 (dd, 1H, J = 8.0, 2.0Hz), 7.16 (d, 1H, J = 1.6 Hz), 6.30 (d, 1H, J = 7.2 Hz), 5.99 (d, 1H, J= 5.6 Hz), 3.80-3.70 (m, 1H), 3.60-3.50 (m, 4H), 3.48-3.40 (m, 4H), 2.91(s, 3H), 2.90-2.80 (m, 2H), 2.78-2.70 (m, 2H), 2.00-1.88 (m, 2H),1.86-1.74 (m, 2H), 1.08 (d, 6H, J = 6.4 Hz). 786

478 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.60 (d, 1H, J = 1.5 Hz),8.29 (d, 1H, J = 1.0 Hz), 7.96- 7.93 (m, 2H), 7.80 (dd, 1H, J = 8.0, 2.0Hz), 7.18 (d, 1H, J = 1.5 Hz), 6.31 (d, 1H, J = 7.0 Hz), 6.00 (d, 1H, J= 5.5 Hz), 3.81-3.75 (m, 1H), 3.54-3.53 (m, 4H), 3.46-3.45 (m, 4H),3.17-3.14 (m, 1H), 3.03-3.01 (m, 1H), 3.01 (s, 3H), 3.00-2.92 (m, 1H),2.70-2.64 (m, 1H), 2.18 (m, 1H), 2.07-2.02 (m, 1H), 1.75-1.72 (m, 1H),1.60-1.58 (m, 1H), 1.08 (d, 6H, J = 6.5 Hz). 787

479 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.4 Hz),8.28 (d, 1H, J = 1.6 Hz), 7.95- 7.90 (m, 2H), 7.79 (dd, 1H, J = 8.4, 2.4Hz), 7.17 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 4.09 (q, 2H, J= 7.2 Hz), 3.64-3.60 (m, 4H), 3.50-3.45 (m, 4H), 3.22-3.18 (m, 1H),3.11-3.07 (m, 1H), 2.92-2.84 (m, 2H), 2.78- 2.74 (m, 1H), 2.51-2.50 (m,1H), 2.05-1.99 (m, 2H), 1.54-1.53 (m, 1H), 1.44-1.43 (m, 1H), 1.22 (t,3H, J = 7.2 Hz), 1.12 (t, 3H, J = 7.2 Hz). 788

470 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.31 (s, 1H), 8.29 (d, 1H, J = 2.0 Hz), 7.97-7.91 (m, 2H), 7.79 (dd, 1H,J = 8.4, 2.4 Hz), 7.17 (d, 1H, J = 1.6 Hz), 5.99 (d, 1H, J = 5.2 Hz),4.08 (q, 2H, J = 7.2 Hz), 3.68- 3.56 (m, 4H), 3.52-3.42 (m, 4H),3.26-3.12 (m, 2H), 3.10-2.98 (m, 2H), 2.97-2.90 (m, 1H), 2.76-2.64 (m,1H), 2.20-2.00 (m, 2H), 1.84- 1.68 (m, 1H), 1.66-1.54 (m, 1H), 1.21 (t,3H, J = 6.8 Hz), 1.13 (t, 3H, J = 6.8 Hz). 789

480 1H-NMR (H-NMR (500 MHz, 4d-MeOD) δ ppm 7.97 (d, 1H, J = 1.5 Hz),7.86 (d, 1H, J = 5.0 Hz), 7.71 (d, 2H, J = 8.5 Hz), 7.32 (d, 2H, J = 8.5Hz), 6.90 (d, 1H, J = 1.5 Hz), 6.02 (d, 1H, J = 5.5 Hz), 4.85-4.81 (m,1H), 4.26-4.23 (m, 1H), 4.16-4.13 (m, 1H), 3.91-3.86 (m, 1H), 3.78- 3.71(m, 4H), 3.61-3.59 (m, 1H), 3.55-3.51 (m, 6H), 3.14 (td, 2H, J = 12.52.5 Hz), 2.93 (tt, 1H, J = 12.5, 3.5 Hz), 2.12-2.09 (m, 2H), 1.98- 1.89(m, 2H). 790

480 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.38 (s, 1H), 8.16 (s, 1H),7.91 (d, 1H, J = 5.0 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0Hz), 7.01 (s, 1H), 5.99 (d, 1H, J = 5.5 Hz), 4.62 (quintet, 1H, J = 5.5Hz), 3.60-3.55 (m, 12H), 3.20-3.14 (m, 2H), 2.81-2.28 (m, 3H), 2.74-2.71(m, 1H), 1.91-1.89 (m, 1H), 1380- 1.78 (m, 1H), 1.69-1.64 (m, 2H). 791

481 792

481 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz,2H), 6.90 (d, J = 1.9 Hz, 1H), 6.01 (d, J = 5.5 Hz, 1H), 5.41 (tt, J =6.3, 5.1 Hz, 1H), 4.90 (ddd, J = 7.3, 6.2, 0.9 Hz, 2H), 4.70-4.59 (m,2H), 3.92 (t, J = 6.3 Hz, 1H), 3.87-3.59 (m, 7H), 3.53 (t, J = 5.2 Hz,4H), 2.81-2.68 (m, 1H), 1.07 (dd, J = 15.0, 6.3 Hz, 6H). 793

484 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.61 (d, 1H, J = 1.6 Hz),8.36 (s, 1H), 8.31 (d, 1H, J = 1.6 Hz), 7.97-7.93 (m, 2H), 7.82-7.79 (m,1H), 7.19 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 6.4 Hz), 3.64-3.60 (m,4H), 3.52-3.44 (m, 4H), 3.23-3.19 (m, 2H), 3.14-3.04 (m, 2H), 3.00- 2.95(m, 1H), 2.77-2.70 (m, 1H), 2.20-2.02 (m, 2H), 1.82-1.61 (m, 2H), 1.14(t, 3H, J = 7.2 Hz). 794

484 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.61 (d, 1H, J = 1.6 Hz),8.36 (s, 1H), 8.31 (d, 1H, J = 1.6 Hz), 7.97-7.93 (m, 2H), 7.82-7.79 (m,1H), 7.19 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 6.4 Hz), 3.64-3.60 (m,4H), 3.52-3.44 (m, 4H), 3.24-3.19 (m, 2H), 3.12-3.03 (m, 2H), 3.00- 2.94(m, 1H), 2.77-2.70 (m, 1H), 2.20-2.02 (m, 2H), 1.82-1.60 (m, 2H), 1.14(t, 3H, J = 7.2 Hz). 795

489 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.93 (d, J = 1.8 Hz, 1H),7.83 (d, J = 5.5 Hz, 1H), 7.73- 7.56 (m, 2H), 7.30-7.19 (m, 2H), 6.85(d, J = 1.8 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 4.17- 4.00 (m, 1H), 3.69(s, 4H), 3.48 (d, J = 7.0 Hz, 4H), 3.19-2.99 (m, 3H), 2.82 (p, J = 6.6Hz, 1H),2.68-2.47 (m, 1H), 2.40 (t, J = 11.6 Hz, 2H), 1.98-1.67 (m, 4H),1.14 (d, J = 6.6 Hz, 6H), 0.77-0.64 (m, 4H). 796

465 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 1.5 Hz),8.32 (s, 1H), 8.30 (d, 1H, J = 1.5 Hz), 7.96-7.94 (m, 2H), 7.79 (dd, 1H,J = 8.5, 2.0 Hz), 7.18 (d, 1H, J = 1.5 Hz), 6.00 (d, 1H, J = 5.5 Hz),4.09 (q, 2H, J = 6.5 Hz), 3.62- 3.61 (m, 4H), 3.49-3.48 (m, 4H),3.16-3.13 (m, 1H), 3.00 (s, 3H), 2.95-2.92 (m, 2H), 2.70-2.65 (m, 1H),2.18-2.15 (m, 1H), 2.07-2.02 (m, 1H), 1.75-1.73 (m, 1H), 1.60-1.57 (m,1H), 1.22 (t, 3H, J = 6.5 Hz). 797

492 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.61 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.6 Hz), 7.97- 7.92 (m, 2H), 7.81 (dd, 1H, J = 8.4, 2.4Hz), 7.18 (d, 1H, J = 1.6 Hz), 6.33 (d, 1H, J = 7.6 Hz), 6.01 (d, 1H, J= 5.6 Hz), 3.80-3.78 (m, 1H), 3.54-3.53 (m, 4H), 3.46-3.45 (m, 4H),3.25-3.18 (m, 2H), 3.17-3.07 (m, 2H), 3.05- 2.97 (m, 2H), 2.70-2.63 (m,1H), 2.10-2.01 (m, 2H), 1.76-1.75 (m, 1H), 1.74-1.73 (m, 1H), 1.14 (t,3H, J = 6.8 Hz), 1.08 (d, 6H, J = 6.8 Hz). 798

492 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 1.6 Hz),8.30-8.25 (m, 2H), 8.00-7.90 (m, 2H), 7.79 (dd, 1H, J = 8.4, 2.0 Hz),7.17 (d, 1H, J = 1.6 Hz), 6.30 (d, 1H, J = 8.4 Hz), 5.99 (d, 1H, J = 5.6Hz), 3.84-3.70 (m, 1H), 3.56-3.50 (m, 4H), 3.48-3.40 (m, 4H), 3.26- 3.16(m, 1H), 3.14-3.04 (m, 2H), 3.02-2.86 (m, 2H), 2.72-2.60 (m, 1H),2.18-1.94 (m, 2H), 1.80-1.64 (m, 1H), 1.62-1.50 (m, 1H), 1.13 (t, 3H, J= 6.8 Hz), 1.07 (d, 6H, J = 6.8 Hz). 799

493 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.21 (s, 1H), 7.93 (d, 1H, J= 5.2 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 7.06 (s,1H), 6.01 (d, 1H, J = 5.6 Hz), 5.35 (quintet, 1H, J = 5.2 Hz), 4.80 (t,2H, J = 6.8 Hz), 4.55-4.52 (m, 2H), 3.75-3.70 (m, 4H), 3.70-3.65 (m,2H), 3.65-3.60 (m, 2H), 3.50-3.49 (m, 4H), 2.91 (s, 3H), 1.99-1.94 (m,4H). 800

493 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.61 (d, 1H, J = 1.5 Hz),8.32 (d, 1H, J = 2.0 Hz), 7.99- 7.95 (m, 2H), 7.81 (d, 1H, J = 9.5 Hz),7.20 (d, 1H, J = 1.5 Hz), 6.02 (d, 1H, J = 4.5 Hz), 5.34 (quintet, 1H, J= 5.5 Hz), 4.80 (t, 2H, J = 7.5 Hz), 4.53 (dd, 2H, J = 7.5, 5.5 Hz),3.71-3.65 (m, 2H), 3.65-3.60 (m, 2H), 3.53-3.51 (m, 4H), 3.34-3.31 (m,1H), 3.13-3.06 (m, 2H), 3.01 9s, 3H), 2.82-2.77 (m, 1H), 2.24-2.21 (m,1H), 2.11-2.06 (m, 1H), 1.83-1.80 (m, 1H), 1.72- 1.69 (m, 1H). 801

493 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.2 Hz), 7.94 (d, 1H, J = 5.6 Hz), 7.92 (d, 1H, J = 8.8Hz), 7.77 (dd, 1H, J = 8.4, 2.4 Hz), 7.17 (d, 1H, J = 2.0 Hz), 6.00 (d,1H, J = 5.6 Hz), 5.40-5.25 (m, 1H), 4.78 (t, 2H, J = 7.2 Hz), 4.55-4.50(m, 2H), 3.80-3.72 (m, 2H), 3.72-3.65 (m, 2H), 3.54-3.46 (m, 4H), 2.97(s, 3H), 2.96-2.91 (m, 1H), 2.90-2.82 (m, 1H), 2.80-2.72 (m, 1H),2.56-2.51 (m, 1H), 2.15-2.05 (m, 1H), 2.05- 1.95 (m, 1H), 1.70-1.55 (m,1H), 1.50-1.35 (m, 1H). 802

494 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.59- 8.47 (m, 1H), 8.20 (d,J = 1.8 Hz, 1H), 8.00- 7.77 (m, 3H), 7.16 (d, J = 1.8 Hz, 1H), 6.02 (d,J = 5.5 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.73 (d, J = 5.4 Hz, 4H),3.54 (dd, J = 6.6, 3.9 Hz, 4H), 3.28-3.14 (m, 1H), 3.00 (s, 3H), 2.94-2.82 (m, 1H), 2.25-2.05 (m, 2H), 1.91 (td, J = 13.1, 4.3 Hz, 1H), 1.66(d, J = 14.2 Hz, 1H), 1.40 (s, 3H), 1.29 (t, J = 7.1 Hz, 4H), 1.14 (s,3H) 803

494 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.37- 8.28 (m, 1H), 7.95 (dd,J = 3.6, 1.8 Hz, 1H), 7.85 (dd, J = 5.4, 3.6 Hz, 1H), 7.76-7.62 (m, 2H),7.51-7.33 (m, 1H), 7.28 (d, J = 7.9 Hz, 2H), 6.90 (dd, J = 3.9, 1.8 Hz,1H), 6.88-6.68 (m, 1H), 6.10-5.98 (m, 1H), 3.97 (s, 1H), 3.80 (d, J =18.0 Hz, 1H), 3.62 (s, 4H), 3.14- 3.04 (m, 3H), 2.88 (d, J = 15.9 Hz,1H), 2.60 (t, J = 12.2 Hz, 1H), 2.43 (d, J = 12.3 Hz, 2H), 2.00-1.73 (m,5H), 1.28 (s, 1H), 1.16 (d, J = 6.5 Hz, 6H). 804

495 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.97 (d, J = 1.8 Hz, 1H),7.84 (d, J = 5.4 Hz, 1H), 7.76- 7.64 (m, 2H), 7.59-7.47 (m, 2H), 6.90(d, J = 1.8 Hz, 1H), 6.01 (d, J = 5.5 Hz, 1H), 5.41 (tt, J = 6.2, 5.1Hz, 1H), 4.90 (ddd, J = 7.5, 5.1, 1.0 Hz, 2H), 3.76 (d, J = 36.2 Hz,5H), 3.61 (d, J = 13.2 Hz, 1H), 3.57-3.48 (m, 4H), 2.82-2.73 (m, 1H),1.57 (s, 3H), 1.03 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H). 805

495 806

495 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.30- 8.28 (m, 2H), 7.92 (d,1H, J = 5.6 Hz), 7.72 (s, 1H), 7.69-7.67 (m, 1H), 7.39 (t, 1H, J = 7.2Hz), 7.12 (d, 1H, J = 2.0 Hz), 6.32 (d, 1H, J = 7.5 Hz), 5.99 (d, 1H, J= 5.6 Hz), 3.80-3.76 (m, 1H), 3.54-3.52 (m, 4H), 3.46-3.44 (m, 4H),3.26-3.22 (m, 1H), 3.05 (s, 3H), 3.05-2.96 (m, 2H), 2.68-2.64 (m, 1H),2.24-2.20 (m, 1H), 2.09-2.04 (m, 1H), 1.77-1.75 (m, m1H), 1.59- 1.56 (m,1H), 1.09-1.03 (d, 6H, J = 6.8 Hz). 807

495 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.30- 8.28 (m, 2H), 7.92 (d,1H, J = 5.5 Hz), 7.72 (s, 1H), 7.68 (d, 1H, J = 7.0 Hz), 7.38 (t, 1H, J= 7.5 Hz), 7.12 (d, 1H, J = 1.5 Hz), 6.32 (d, 1H, J = 7.5 Hz), 5.99 (d,1H, J = 5.5 Hz), 3.80-3.76 (m, 1H), 3.54-3.52 (m, 4H), 3.46-3.44 (m,4H), 3.26-3.22 (m, 2H), 3.05 (s, 3H), 3.05-2.96 (m, 2H), 2.68-2.64 (m,1H), 2.24-2.20 (m, 1H), 2.09-2.04 (m, 1H), 1.77-1.75 (m, 1H), 1.59- 1.56(m, 1H), 1.09-1.03 (d, 6H, J = 6.5 Hz). 808

498 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (d, 1H, J = 1.6 Hz),7.92 (d, 1H, J = 5.6 Hz), 7.85 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4Hz), 7.09 (d, 1H, J = 2.0 Hz), 6.00 (d, 1H, J = 5.6 Hz), 4.00-3.82 (m,2H), 3.82-3.65 (m, 2H), 3.57-3.52 (m, 2H), 3.52-3.47 (m, 2H), 2.87- 2.80(m, 2H), 2.50-2.25 (m, 4H), 2.10-1.95 (m, 1H), 1.95-1.75 (m, 2H),0.82-0.74 (m, 4H). 809

499 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.31 (s, 1H), 8.21 (d, 1H, J= 1.6 Hz), 7.91 (d, 1H, J = 5.6 Hz), 7.83 (d, 2H, J = 8.0 Hz), 7.41 (s,2H, J = 8.4 Hz), 7.05 (d, 1H, J = 1.6 Hz), 5.97 9d, 1H, J = 5.6 Hz),3.70-3.62 (m, 3H), 3.54-3.53 (m, 2H), 3.47-3.45 (m, 4H), 3.32-3.25 (m,1H), 3.16-3.13 (m, 2H), 3.05-3.02 (m, 1H), 2.97 (s, 3H), 2.91-2.87 (m,1H), 2.73-2.58 (m, 3H), 2.49-2.45 (m, 2H), 2.17-2.14 (m, 1H), 2.05- 1.97(m, 2H), 1.81-1.70 (m, 1H), 1.63-1.59 (m, 1H). 810

501 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.2 Hz),7.89 (d, 1H, J = 5.2 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz), 4.22 (t, 2H, J= 6.0 Hz), 3.740-3.56 (m, 4H), 3.52-3.42 (m, 4H), 2.91 (t, 2H, J = 6.0Hz), 2.82-2.77 (m, 2H), 2.74-2.65 (m, 2H), 2.22-2.08 (m, 2H), 1.86-1.66(m, 2H), 1.62- 1.38 (m, 2H), 1.00-0.90 (m, 6H). 811

503 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.13 (d, J = 1.8Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.34 (d, J= 8.5 Hz, 2H), 7.00 (d, J = 1.9 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 4.51(s, 1H), 3.91 (s, 2H), 3.69 (s, 2H), 3.50 (d, J = 25.3 Hz, 4H), 2.59 (t,J = 6.5 Hz, 2H), 2.32-2.18 (m, 2H), 2.08-1.95 (m, 3H), 1.84 (t, J = 11.2Hz, 2H), 0.89 (d, J = 6.5 Hz, 6H), 0.83-0.66 (m, 4H). 812

503 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.94 (d, J = 1.8 Hz, 1H),7.83 (d, J = 5.4 Hz, 1H), 7.72- 7.60 (m, 2H), 7.31-7.22 (m, 2H), 6.89(d, J = 1.8 Hz, 1H), 5.99 (d, J = 5.5 Hz, 1H), 5.48 (s, 0H), 4.00 (t, J= 8.2 Hz, 1H), 3.91 (dd, J = 8.3, 6.0 Hz, 2H), 3.88-3.80 (m, 5H), 3.57(t, J = 5.1 Hz, 2H), 3.55-3.46 (m, 3H), 3.17-3.02 (m, 2H), 2.86 (p, J =6.6 Hz, 1H), 2.58 (ddt, J = 11.8, 7.9, 4.0 Hz, 1H), 2.44 (dd, J = 13.0,10.3 Hz, 2H), 2.26-2.08 (m, 2H), 1.91 (d, J = 12.9 Hz, 2H), 1.82 (qd, J= 12.4, 3.7 Hz, 2H), 1.15 (d, J = 6.6 Hz, 6H). 813

503 814

506 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.95 (d, J = 1.8 Hz, 1H),7.85 (d, J = 5.5 Hz, 1H), 7.68 (d, J = 1.8 Hz, 2H), 7.29 (d, J = 8.1 Hz,2H), 6.88 (d, J = 1.8 Hz, 1H), 6.01 (d, J = 5.5 Hz, 1H), 4.89 (d, J =7.7 Hz, 2H), 4.65 (d, J = 7.8 Hz, 2H), 3.80 (s, 2H), 3.58-3.49 (m, 4H),2.76 (s, 5H), 2.03 (s, 2H), 1.91 (d, J = 12.2 Hz, 1H), 1.27 (d, J = 6.7Hz, 6H). 815

506 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.2 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4Hz), 7.03 (s, 1H), 6.00 (d, 1H, J = 5.6 Hz), 5.33 (quintet, 1H, J = 5,6Hz), 4.79 (t, 2H, J = 7.2 Hz), 4.53 (dd, 2H, J = 7.2, 5.6 Hz), 3.72-3.66(m, 2H), 3.66-3.60 (m, 2H), 3.55-3.48 (m, 4H), 3.18-3.16 (m, 1H),3.08-3.04 (m, 1H), 2.90- 2.87 (m, 2H), 2.69-2.65 (m, 1H), 2.51-2.50 (m,1H), 2.06-2.05 (m, 12H), 1.96-1.95 (m, 1H), 1.55-1.52 (m, 1H), 1.46-1.45(m, 1H), 1.11 (t, 3H, J = 6.8 Hz). 816

506 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.2 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.2 Hz), 5.99 (d, 1H, J = 5.6 Hz), 5.34 (quintet,1H, J = 5.6 Hz), 4.79 (t, 2H, J = 7.2 Hz), 4.53 (dd, 1H, J = 7.2, 5.6Hz), 3.72-3.65 (m, 2H), 3.65-3.57 (m, 2H), 3.54- 3.44 (m, 4H), 3.20-3.15(m, 1H), 3.08-3.03 (m, 1H), 2.95-2.88 (m, 2H), 2.73-2.68 (m, 1H),2.54-2.50 (m, 1H), 2.08-2.04 (m, 1H), 2.00- 1.95 (m, 1H), 1.70-1.62 (m,1H), 1.50-1.44 (m, 1H), 1.11 (t, 3H, J = 7.2 Hz). 817

506 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.54 (t, J = 1.6 Hz, 1H),8.20 (d, J = 1.8 Hz, 1H), 7.88 (dd, J = 3.5, 1.8 Hz, 3H), 7.17 (d, J =1.8 Hz, 1H), 6.00 (d, J = 5.6 Hz, 1H), 3.93 (hept, J = 6.4 Hz, 1H), 3.65(dd, J = 6.7, 3.5 Hz, 4H), 3.60-3.48 (m, 5H), 3.01 (s, 4H), 2.31-2.11(m, 2H), 2.06-2.87 (m, 1H), 1.73 (d, J = 1.4 Hz, 1H), 1.47 (s, 3H), 1.22(s, 3H), 1.17 (d, J = 6.6 Hz, 6H). 818

507 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.60 (d, 1H, J = 2.0 Hz),8.35-8.25 (m, 2H), 8.00-7.90 (m, 2H), 7.80 (dd, 1H, J = 8.4, 2.4 Hz),7.19 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.6 Hz), 5.33 (quintet, 1H, J= 5.6 Hz), 4.78 (t, 2H, J = 7.2 Hz), 4.56-4.50 (m, 2H), 3.70-3.65 (m,2H), 3.65-3.59 (m, 2H), 3.54-3.46 (m, 4H), 3.26- 3.14 (m, 2H),3.12-23.00 (m, 2H), 2.98-2.90 (m, 1H), 2.78-2.64 (m, 1H), 2.20-2.11 (m,1H), 2.10-2.00 (m, 1H), 1.84-1.70 (m, 1H), 1.66- 1.56 (m, 1H), 1.13 (t,3H, J = 7.2 Hz). 819

507 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ p-pm 8.60 (d, 1H, J = 1.6 Hz),8.30 (d, 1H, J = 2.0 Hz), 7.96- 7.91 (m, 2H), 7.80 (dd, 1H, J = 8.4, 2.4Hz), 7.19 (d, 1H, J = 1.,6 Hz), 6.01 (d, 1H, J = 5.6 Hz), 5.34 (quintet,1H, J = 5.2 Hz), 4.79 (t, 2H, J = 7.2 Hz), 4.53 (dd, 2H, J = 7.2, 5.2Hz), 3.70-3.65 (m, 2H), 3.65-3.60 (m, 2H), 3.52- 3.45 (m, 4H), 3.23-3.18(m, 1H), 3.11-3.05 (m, 2H), 2.98-2.95 (m, 1H), 2.89-2.86 (m, 1H),2.66-2.60 (m, 1H), 2.14-2.10 (m, 2H), 1.73- 1.70 (m, 1H), 1.55-1.52 (m,1H), 1.13 (t, 3H, J = 7.2 Hz). 820

507 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.5 Hz), 8.22 (s, 1H), 7.96-7.91 (m, 2H), 7.78 (dd, 1H,J = 2.0 Hz, 8.0 Hz), 7.18 (d, 1H, J = 1.5 Hz), 6.00 (d, 1H, J = 6.0 Hz),4.09 (q, 2H, J = 6.5 Hz), 3.70-3.55 (m, 4H), 3.55-3.40 (m, 4H), 2.93 (s,3H), 2.90-2.80 (m, 1H), 2.80-2.70 (m, 2H), 2.70-2.55 (m, 2H), 2.15-2.03(m, 2H), 2.03- 1.90 (m, 2H), 1.22 (t, 3H, J = 6.5 Hz), 1.05 (d, 6H, J =6.0 Hz). 821

508 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.60 (d, 1H, J = 1.5 Hz),8.30 (d, 1H, J = 1.5 Hz), 7.96 (s, 1H), 7.95-7.93 (m, 1H), 7.80 (dd, 1H,J = 8.5, 2.0 Hz), 7.19 (d, 1H, J = 1.0 Hz), 6.01 (d, 1H, J = 5.5 Hz),5.33 (quintet, 1H, J = 5.5 Hz), 4.79 (t, 2H, J = 7.0 Hz), 4.53 (dd, 2H,J = 7.0, 5.5 Hz), 3.77-3.74 (m, 2H), 3.74-3.70 (m, 4H), 3.62-3.58 (m,2H), 3.54-3.50 (m, 2H), 3.09 (q, 2H, J = 7.0 Hz), 2.02-1.97 (m, 4H),1.10 (t, 3H, J = 7.0 Hz). 822

512 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.39- 8.24 (m, 2H), 8.03 (d,J = 1.8 Hz, 1H), 7.90 (d, J = 5.4 Hz, 1H), 7.79-7.67 (m, 2H), 7.52- 7.41(m, 2H), 7.41-7.23 (m, 2H), 6.96 (d, J = 1.8 Hz, 1H), 6.08 (d, J = 5.5Hz, 1H), 3.96 (d, J = 16.6 Hz, 2H), 3.87 (d, J = 27.2 Hz, 2H), 3.70-3.57(m, 5H), 3.57-3.37 (m, 4H), 3.15- 2.97 (m, 2H), 2.95-2.75 (m, 1H), 2.13(d, J = 13.9 Hz, 2H), 2.08-1.96 (m, 2H), 1.93 (s, 3H), 1.40-1.31 (m,8H), 1.23-1.12 (m, 3H). 823

515 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (d, 1H, J = 2.0 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.86 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4Hz), 7.06 (d, 1H, J = 1.6 Hz), 6.32 (d, 1H, J = 7.2 Hz), 6.00 (d, 1H, J= 5.6 Hz), 3.85-3.70 (m, 1H), 3.55-3.50 (m, 4H), 3.50-3.45 (m, 4H),2.91-2.87 (m, 2H), 2.50-2.25 (m, 4H), 1.95- 1.80 (m, 2H), 1.08 (d, 6H, J= 7.2 Hz). 824

517 1H-NMR (H NMR (500 MHz, Methanol-d4) δ 8.01 (d, J = 1.8 Hz, 1H),7.88 (d, J = 5.4 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.1 Hz,2H), 6.96 (d, J = 1.9 Hz, 1H), 6.03 (d, J = 5.4 Hz, 1H), 5.51 (s, 0H),4.06 (s, 2H), 3.87 (s, 2H), 3.74 (q, J = 6.6 Hz, 4H), 3.68 (d, J = 24.2Hz, 2H), 3.58 (s, 2H), 3.23 (q, J = 7.6 Hz, 5H), 2.88 (s, 0H), 2.50 (s,2H), 2.28 (s, 2H), 2.05 (dd, J = 8.9, 4.3 Hz, 1H), 1.25 (d, J = 6.5 Hz,6H), 0.95 (q, J = 3.3 Hz, 2H), 0.91-0.86 (m, 2H). 825

518 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.19-5.14 (m,1H), 3.83-3.76 (m, 2H), 3.76-3.68 (m, 2H), 3.65-3.55 (m, 4H), 3.50- 3.40(m, 4H), 2.80-2.75 (m, 2H), 2.72-2.65 (m, 2H), 2.20-2.05 (m, 3H),2.00-1.88 (m, 1H), 1.86-1.76 (m, 1H), 1.75-1.68 (m, 1H), 1.59- 1.49 (m,1H), 1.49-1.40 (m, 1H), 1.00-0.94 (m, 6H). 826

518 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.6 Hz),7.89 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4Hz), 6.99 (d, 1H, J = 1.6 Hz), 5.97 (d, 1H, J = 5.6 Hz), 5.19-5.14 (m,1H), 3.83-3.76 (m, 2H), 3.76-3.68 (m, 2H), 3.65-3.55 (m, 4H), 3.50- 3.40(m, 4H), 2.80-2.75 (m, 2H), 2.72-2.65 (m, 2H), 2.20-2.05 (m, 3H),2.00-1.88 (m, 1H), 1.86-1.76 (m, 1H), 1.75-1.68 (m, 1H), 1.59- 1.49 (m,1H), 1.49-1.40 (m, 1H), 1.00-0.94 (m, 6H). 827

518 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.13 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 6.98 (d, 1H, J = 2.0 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.65 (d, 2H, J= 7.2 Hz), 4.41 (d, 2H, J = 7.2 Hz), 3.65-3.60 (m, 2H), 3.60-3.54 (m,2H), 3.52-3.42 (m, 4H), 2.83-2.74 (m, 2H), 2.72- 2.66 (m, 2H), 2.22-2.08(m, 2H), 1.86-1.68 (m, 2H), 1.66 (s, 3H), 1.60-1.36 (m, 2H), 1.00-0.94(m, 6H). 828

518 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, J = 1.0 Hz),7.90 (d, 1H, J = 5.5 Hz), 7.72 (d, 2H, J = 8.5 Hz), 7.27 (d, 2H, J = 8.0Hz), 7.00-6.99 (m, 1H), 5.99 (d, 1H, J = 5.5 Hz), 5.40-5.30 (m, 0.25H),5.05-4.95 (m, 0.25H), 4.95-4.85 (m, 0.75H), 4.74-4.61 (m, 1H), 4.60-4.55 (m, 0.75H), 4.45-4.35 (m, 1H), 3.65-3.60 (m, 2H), 3.60-3.55 (m,2H), 3.52-3.45 (m, 4H), 2.90-2.80 (m, 2H), 2.80-2.70 (m, 2H), 2.25- 2.10(m, 2H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 1H), 1.6-1.50 (m, 1H),1.50-1.40 (m, 1H), 1.38 (d, 2.25H, J = 6.5 Hz), 1.30 (d, 0.75H, J = 6.5Hz), 1.05-0.90 (m, 6H). 829

519 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (s, 1H), 7.89 (d, 1H, J= 5 6 Hz), 7.79 (d, 2H, J = 7.6 Hz), 7.39 (d, 2H, J = 8.4 Hz), 7.03 (s,1H), 6.31 (s, 1H), 5.98 (d, 1H, J = 5.2 Hz), 3.81- 3.76 (m, 1H),3.53-3.50 (m, 4H), 3.45-3.42 (m, 4H), 2.89 (s, 3H), 2.71-2.67 (m, 1H),2.60-2.58 (m, 2H), 2.48-2.46 (m, 2H), 1.99-1.96 (m, 2H), 1.87-1.81 (m,2H), 1.08 (d, 6H, J = 6.4 Hz), 0.99 (d, 6H, J = 6.8 Hz). 830

521 1H-NMR (H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.19 (d, J = 1.8Hz, 1H), 7.91 (d, J = 5.4 Hz, 1H), 7.80 (dd, J = 8.0, 5.9 Hz, 2H), 7.36(d, J = 8.5 Hz, 2H), 7.03 (d, J = 1.9 Hz, 1H), 5.99 (d, J = 5.6 Hz, 1H),4.88-4.76 (m, 1H), 3.90- 3.74 (m, 2H), 3.60-3.53 (m, 2H), 3.46 (t, J =5.2 Hz, 5H), 3.11 (d, J = 12.6 Hz, 2H), 2.94 (s, 0H), 2.79 (t, J = 11.9Hz, 2H), 1.99 (t, J = 12.3 Hz, 2H). 831

520 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.30 (s, 1H), 8.18 (s, 1H),7.91 (d, 1H, J = 5.0 Hz), 7.89 (d, 2H, J = 8.5 Hz), 7.40 (d, 2H, J = 8.5Hz), 7.03 (s, 1H), 5.98 (d, 1H, J = 5.0 Hz), 4.09 (q, 2H, J = 7.0 Hz),4.65-4.55 (m, 4H), 4.51-4.41 (m, 4H), 3.06 (q, 2H, J = 6.5 Hz),2.82-2.77 (m, 1H), 2.72-2.68 (m, 2H), 2.63- 2.56 (m, 2H), 2.03-1.98 (m,2H), 1.93-1.88 (m, 2H), 1.22 (t, 3H, J = 6.5 Hz), 1.07 (t, 3H, J = 7.0Hz), 1.03 (d, 6H, J = 7.0 Hz). 832

521 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.98 (d, J = 1.8 Hz, 1H),7.86 (d, J = 5.4 Hz, 1H), 7.76- 7.62 (m, 2H), 7.34-7.22 (m, 2H), 6.91(d, J = 1.8 Hz, 1H), 6.01 (d, J = 5.4 Hz, 1H), 5.14- 5.01 (m, 2H),4.66-4.54 (m, 3H), 3.78 (s, 4H), 3.60-3.47 (m, 4H), 3.34 (s, 4H), 3.10-2.99 (m, 2H), 2.80 (h, J = 6.5 Hz, 1H), 2.62 (p, J = 1.9 Hz, 1H), 2.56(dq, J = 11.9, 4.0 Hz, 1H), 2.38 (td, J = 11.8, 2.7 Hz, 2H), 1.96- 1.68(m, 4H), 1.14 (d, J = 6.6 Hz, 6H). 833

522 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.54 (t, J = 1.5 Hz, 1H),8.20 (d, J = 1.8 Hz, 1H), 8.01- 7.79 (m, 3H), 7.16 (d, J = 1.8 Hz, 1H),6.02 (d, J = 5.5 Hz, 1H), 5.42 (tt, J = 6.2, 5.1 Hz, 1H), 4.90 (ddd, J =7.3, 6.2, 0.9 Hz, 2H), 4.66 (ddd, J = 7.5, 5.1, 0.9 Hz, 2H), 3.77 (d, J= 35.0 Hz, 5H), 3.56 (t, J = 5.2 Hz, 4H), 3.48 (q, J = 7.0 Hz, 1H),3.26-3.07 (m, 1H), 3.00 (s, 3H), 2.87 (dt, J = 13.2, 3.6 Hz, 1H),2.22-2.00 (m, 3H), 1.96-1.78 (m, 1H), 1.65 (d, J = 14.2 Hz, 1H), 1.40(s, 3H), 1.20-1.11 (m, 4H). 834

521 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.6 Hz), 7.96- 7.90 (m, 2H), 7.78 (dd, 1H, J = 8.4, 2.4Hz), 7.17 (m, 2H), 7.78 (dd, 1H, J = 8.4, 2.4 Hz), 7.17 (d, 1H, J = 2.0Hz), 5.99 (d, 1H, J = 5.6 Hz), 4.60-4.50 (m, 2H), 4.48-4.40 (m, 2H),4.08 (q, 2H, J = 7.2 Hz), 3.66-3.56 (m, 4H), 3.52-3.38 (m, 5H), 2.91 (s,3H), 2.60-2.52 (m, 2H), 2.20-2.10 (m, 2H), 2.05-1.85 (m, 4H), 1.21 (t,3H, J = 6.8 Hz). 835

521 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.5 Hz),8.28 (d, 1H, J = 2.0 Hz), 7.94- 7.91 (m, 2H), 7.78 (dd, 1H, J = 8.0, 2.0Hz), 7.17 (d, 1H, J = 1.5 Hz), 6.00 (d, 1H, J = 5.5 Hz), 4.09 (q, 2H, J= 7.0 Hz), 3.62-3.61 (m, 4H), 3.49-3.48 (m, 4H), 3.08 (q, 2H, J = 7.0Hz), 2.69-2.68 (m, 1H), 2.62-2.60 (m, 2H), 2.53-2.51 (m, 2H), 2.01-1.98(m, 2H), 1.91- 1.89 (m, 2H), 1.22 (d, 3H, J = 7.0 Hz), 1.08 (t, 3H, J =7.0 Hz), 1.00-0.99 (m, 6H). 836

522 1H-NMR (H-NMR (500 MHz, 4d-MeOD) δ ppm 7.95 (d, 1H, J = 1.5 Hz),7.83 (d, 1H, J = 5.0 Hz), 7.65 (d, 2H, J = 8.5 Hz), 7.27 (d, 2H, J = 8.5Hz), 6.86 (d, 1H, J = 1.5 Hz), 5.98 (d, 1H, J = 5.5 Hz), 4.85-4.81 (m,0.5H), 4.26-4.13 (m, 1H), 3.90-3.86 (m, 0.5H), 3.78-3.71 (m, 6H), 3.61-3.60 (m, 1H), 3.52-3.49 (m, 4H), 3.06-3.03 (m, 2H), 2.81-2.76 (m, 1H),2.57-2.52 (m, 1H), 2.38-2.32 (m, 2H), 1.89-1.87 (m, 2H), 1.85- 1.79 (m,2H), 1.13 (d, 6H, J = 6.5 Hz) 837

522 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.27 (s, 1H), 8.18 (d, 1H, J= 2.4 Hz), 7.90 (d, 1H, J = 5.2 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.29 (d,2H, J = 8.4 Hz), 7.00 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.2 Hz),4.62 (quintet, 1H, J = 5.2 Hz), 3.57-3.47 (m, 12H, mixed with H2O peak),2.99-2.95 (m, 2H), 2.95-2.91 (m, 1H), 2.81- 2.80 (m, 1H), 2.43-2.36 (m,2H), 1.58-1.77 (m, 2H), 1.69-1.60 (m, 1H), 1.53-1.47 (m, 1H), 1.07-1.04(m, 6H). 838

524 839

527 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (d, 1H, J = 1.6 Hz),7.99 (d, 2H, J = 5.6 Hz), 7.92 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H, J = 1.6Hz), 7.75 (dd, 1H, J = 8.4, 2.0 Hz), 7.13 (d, 1H, J = 1.6 Hz), 6.03 (d,1H, J = 5.6 Hz), 3.93-3.91 (m, 2H), 3.72-3.70 (m, 2H), 3.59-3.58 (m,2H), 3.53-3.51 (m, 2H), 2.91 (s, 3H), 2.72-2.68 (m, 1H), 2.63-2.59 (m,2H), 2.48-2.44 (m, 2H), 2.04-1.99 (m, 3H), 1.91-1.85 (m, 2H), 1.01 (d,6H, J = 6.8 Hz), 0.79-0.73 (m, 4H). 840

529 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.15 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4Hz), 7.00 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J = 5.2 Hz), 5.01 (d, 2H, J= 8.8 Hz), 4.82 (d, 2H, J = 8.8 Hz), 3.73-3.68 (m, 2H), 3.66-3.60 (m,2H), 3.55-3.45 (m, 4H), 2.85-2.75 (m, 2H), 2.74- 2.64 (m, 2H), 2.22-2.08(m, 2H), 1.86-1.77 (m, 1H), 1.76-1.66 (m, 1H), 1.60-1.40 (m, 2H),1.00-0.90 (m, 6H). 841

530 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.93 (d, J = 1.7 Hz, 1H),7.82 (d, J = 5.5 Hz, 1H), 7.71- 7.58 (m, 2H), 7.35-7.21 (m, 2H), 6.87(d, J = 1.8 Hz, 1H), 5.97 (d, J = 5.5 Hz, 1H), 4.79 (s, 4H), 4.22 (s,4H), 3.63-3.56 (m, 4H), 3.52 (dd, J = 6.7, 3.5 Hz, 4H), 3.16-3.07 (m,2H), 2.89 (d, J = 10.8 Hz, 1H), 2.60 (t, J = 12.0 Hz, 1H), 2.46 (t, J =11.6 Hz, 2H), 1.93 (d, J = 13.0 Hz, 2H), 1.88-1.74 (m, 2H), 1.16 (d, J =6.6 Hz, 6H). 842

530 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 7.93 (d, J = 1.8 Hz, 1H),7.83 (dd, J = 5.4, 2.9 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.27 (d, J =8.2 Hz, 2H), 6.87 (dd, J = 3.8, 1.8 Hz, 1H), 5.98 (dd, J = 10.4, 5.5 Hz,1H), 5.46 (d, J = 6.7 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.10 (t, J =7.3 Hz, 1H), 3.68-3.60 (m, 1H), 3.60-3.45 (m, 4H), 3.19-3.05 (m, 2H),2.64-2.40 (m, 4H), 1.99- 1.70 (m, 4H), 1.17 (d, J = 6.5 Hz, 6H). 843

530 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (d, 1H, J = 1.6 Hz),7.93 (d, 1H, J = 5.2 Hz), 7.85 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4Hz), 7.06 (d, 1H, J = 1.6 Hz), 6.01 (d, 1H, J = 5.2 Hz), 5.34 (quintet,1H, J = 5.2 Hz), 4.79 (t, 2H, J = 7.2 Hz), 4.53 (dd, 2H, J = 7.2, 5.2Hz), 3.72-3.62 (m, 2H), 3.62-3.56 (m, 2H), 3.52- 3.47 (m, 4H), 2.87-2.80(m, 2H), 2.50-2.25 (m, 4H), 1.95-1.80 (m, 2H). 844

533 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (s, 0.26H), 8.18 (d, 1H,J = 1.6 Hz), 7.90 (d, 1H, J = 4.2 Hz), 7.80 (d, 2H, J = 8.4 Hz), 7.40(d, 2H, J = 8.4 Hz), 7.03 (d, 1H, J = 1.2 Hz), 6.32 (d, 1H, J = 4.0 Hz),5.98 (d, 1H, J = 4.2 Hz), 4.56-4.53 (m, 2H), 4.46-4.43 (m, 2H), 3.80-3.76 (m, 1H), 3.53-3.51 (m, 4H), 3.47-3.43 (m, 4H), 3.43-3.33 (m, 1H),2.89 (s, 3H), 2.53-2.49 (m, 2H), 2.18-2.13 (m, 2H), 2.01-1.92 (m, 4H),1.08 (d, 6H, J = 6.4 Hz). 845

535 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.60 (d, 1H, J = 2.0 Hz),8.30 (d, 1H, J = 1.6 Hz), 7.96- 7.93 (m, 1H), 7.93 (d, 1H, J = 5.6 Hz),7.81 (dd, 1H, J = 8.4, 2.4 Hz), 7.19 (d, 1H, J = 1.6 Hz), 6.00 (d, 1H, J= 5.6 Hz), 4.56 (t, 2H, J = 6.4 Hz), 4.45 (t, 2H, J = 6.4 Hz), 4.10 (q,2H, J = 7.2 Hz), 3.68-3.58 (m, 4H), 3.52-3.43 (m, 4H)m 3.43-3.40 (m,1H), 3.08 (q, 2H, J = 6.8 Hz), 2.60-2.52 (m, 2H), 2.24-2.12 (m, 2H),2.06-1.86 (m, 4H), 1.23 (t, 3H, J = 7.2 Hz), 1.08 (t, 3H, J = 6.8 Hz).846

535 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.31-8.26 (m, 2H), 7.96-7.91 (m, 2H), 7.78 (dd, 1H, J = 2.0 Hz, 8.0 Hz),7.18 (d, 1H, J = 1.5 Hz), 6.00 (d, 1H, J = 5.5 Hz), 5.40-5.30 (m, 1H),4.82-4.75 (m, 2H), 4.58-4.50 (m, 2H), 3.80-3.55 (m, 4H), 3.55- 3.45 (m,4H), 2.93 (s, 3H), 2.85-2.75 (m, 1H), 2.75-2.65 (m, 2H), 2.65-2.55 (m,2H), 2.12- 1.90 (m, 4H), 1.04 (d, 6H, J = 6.5 Hz). 847

536 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.13 (s, 1H), 7.90 (d, 1H, J= 5.5 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.24 (d, 2H, J = 8.0 Hz), 6.99 (s,1H), 5.99 (d, 1H, J = 6.0 Hz), 4.78-4.46 (m, 1H), 3.75-3.65 (m, 4H),3.65-3.58 (m, 2H), 3.51- 3.42 (m, 4H), 3.08-3.00 (m, 2H), 2.93-2.90 (m,1H), 2.56-2.51 (m, 1H), 2.49-2.42 (m, 2H), 1.83-1.79 (m, 2H), 1.79-1.72(m, 2H), 1.08 (d, 6H, J = 7.0 Hz). 848

538 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.5 Hz),7.91 (d, 1H, J = 5.5 Hz), 7.75 (d, 2H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.5Hz), 7.05 (d, 1H, J = 1.5 Hz), 6.49 (t, 1H, J = 76.5 Hz), 5.98 (d, 1H, J= 5.5 Hz), 4.35-4.29 (m, 1H), 3.93-3.91 (m, 2H), 3.72-3.70 (m, 2H),3.54-3.50 (m, 2H), 3.50-3.46 (m, 2H), 2.88- 2.80 (m, 2H), 2.80-2.72 (m,2H), 2.31 (t, 2H, J = 11.0 Hz), 2.12-2.10 (m, 1H), 2.04-2.00 (m, 1H),1.68-1.63 (m, 1H), 0.98-0.95 (m, 6H), 0.79-0.74 (m, 4H). 849

538 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 2.0 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 8.4Hz), 7.04 (d, 1H, J = 1.6 Hz), 6.49 (t, 1H, J = 76.4 Hz), 5.98 (d, 1H, J= 5.6 Hz), 4.35-4.29 (m, 1H), 3.93-3.91 (m, 2H), 3.72-3.70 (m, 2H),3.55-3.50 (m, 2H), 3.50-3.45 (m, 2H), 2.86- 2.79 (m, 2H), 2.79-2.72 (m,2H), 2.31 (t, 2H, J = 11.2 Hz), 2.12-2.10 (m, 1H), 2.04-2.00 (m, 1H),1.68-1.63 (m, 1H), 0.98-0.94 (m, 6H), 0.80-0.74 (m, 4H). 850

538 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 1.6 Hz),8.29 (d, 1H, J = 1.2 Hz), 8.14 (s, 1H), 7.96-7.92 (m, 2H), 7.78 (dd, 1H,J = 8.0, 2.0 Hz), 7.18 (d, 1H, J = 1.6 Hz), 6.31 (d, 1H, J = 7.2 Hz),6.00 (d, 1H, J = 5.6 Hz), 4.60- 4.43 (m, 2H), 3.81-3.77 (m, 1H),3.55-3.51 (m, 4H), 3.50-3.45 (m, 4H), 3.08-3.00 (m, 1H), 2.93 (s, 3H),2.80-2.72 (m, 4H), 2.11-2.00 (m, 2H), 2.00-1.92 (m, 2H), 1.15-1.05 (m,9H). 851

542 1H-NMR (H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 3H), 7.96 (d, J =1.8 Hz, 1H), 7.85 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H),7.56-7.43 (m, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.22-7.07 (m, 3H), 6.91 (d,J = 1.8 Hz, 1H), 6.02 (d, J = 5.6 Hz, 1H), 3.90-3.75 (m, 4H), 3.68-3.58(m, 4H), 3.50 (d, J = 13.0 Hz, 4H), 3.18-3.02 (m, 2H), 2.88 (s, 1H),2.15 (d, J = 14.4 Hz, 3H), 2.00 (t, J = 13.1 Hz, 2H), 1.37 (d, J = 6.6Hz, 6H). 852

544 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.23 (d, 1H, J = 2.0 Hz),7.99 (d, 1H, J = 5.2 Hz), 7.92 (d, 1H, J = 8.8 Hz), 7.82 (d, 1H, J = 1.6Hz), 7.75 (dd, 1H, J = 8.8, 2.0 Hz), 7.12 (d, 1H, J = 1.6 Hz), 6.34 (d,1H, J = 7.6 Hz), 6.05 (d, 1H, J = 5.6 Hz), 3.81-3.75 (m, 1H), 3.52-3.50(m, 4H), 3.46-3.44 (m, 4H), 2.91 (s, 3H), 2.72-2.68 (m, 1H), 2.63-2.59(m, 2H), 2.48-2.44 (m, 2H), 2.01-1.97 (m, 2H), 1.91-1.85 (m, 2H), 1.08(d, 6H, J = 6.8 Hz), 1.00 (d, 6H, J = 6.4 Hz). 853

545 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.14 (d, 1H, mJ = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.71 (d, 2H, J = 7.8 Hz), d, 2H, J = 8.0 Hz),6.99 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 5.11-5.05 (m, 1H),4.43 (dd, 1H, J = 9.6, 7.2 Hz), 4.14 (dd, 1H, J = 10.4, 7.2 Hz), 4.09(dd, 1H, J = 9.6, 4.0 Hz), 3.78 (dd, 1H, J = 10.4, 4.0 Hz), 3.72-3.65(m, 2H), 3.65-3.58 (m, 2H), 3.51-3.45 (m, 4H), 2.83-2.76 (m, 2H),2.73-2.65 (m, 2H), 2.22-2.08 (m, 2H), 1.84- 1.77 (m, 1H), 1.77 (s, 2H),1.76-1.71 (m, 1H), 1.60-1.50 (m, 1H), 1.49-1.39 (m, 1H), 1.00- 0.92 (m,6H). 854

546 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.5 Hz), 8.21 (s, 1H), 7.95-7.92 (m, 2H), 7.79 (dd, 1H,J = 8.5, 2.5 Hz), 7.19 (d, 1H, J = 1.5 Hz), 6.01 (d, 1H, J = 5.0 Hz),4.24 (t, 2H, J = 6.0 Hz), 3.68- 3.64 (m, 4H), 3.53-3.48 (m, 4H), 3.09(q, 2H, J = 7.0 Hz), 2.92 (t, 2H, J = 6.0 Hz), 2.83-2.82 (m, 1H),2.74-2.72 (m, 2H), 2.64-2.60 (m, 2H), 2.06-2.04 (m, 2H), 1.98-1.95 (m,2H), 1.08 (t, 3H, J = 7.0 Hz), 1.05 (d, 6H, J = 7.0 Hz). 855

547 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 1.6 Hz),8.29 (d, 1H, J = 1.6 Hz), 8.17 (s, 1H), 7.95-7.90 (m, 2H), 7.80-7.76 (m,1H), 7.18 (d, 1H, J = 1.6 Hz), 6.01 (d, 1H, J = 5.6 Hz), 5.36-5.31 (m,1H), 4.82-4.76 (m, 2H), 4.55-4.51 (m, 2H), 3.80-3.55 (m, 4H), 3.51- 3.48(m, 4H), 3.10 (q, 2H, J = 7.2 Hz), 2.79- 2.75 (m, 2H), 2.61-2.55 (m,2H), 2.00-1.96 (m, 2H), 1.88-1.84 (m, 2), 1.67-1.65 (m, 1H), 1.10 (t,3H, J = 7.2 Hz), 0.44-0.41 (m, 2H), 0.31-0.29 (m, 2H). 856

547 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.19 (s, 1H), 8.17 (d, 1H, J= 1.6 Hz), 7.90 (d, 1H, J = 5.6 Hz), 7.78 (d, 2H, J = 8.4 Hz), 7.40 (d,2H, J = 8.0 Hz), 7.02 (d, 1H, J = 1.2 Hz), 6.31 (d, 1H, J = 7.6 Hz),5.97 (d, 1H, J = 5.2 Hz), 4.60- 4.50 (m, 2H), 4.48-4.40 (m, 2H),3.80-3.70 (m, 1H), 3.60-3.48 (m, 4H), 3.46-3.36 (m, 5H), 3.03 (q, 2H, J= 6.8 Hz), 2.60-2.50 (m, 2H), 2.22-2.10 (m, 2H), 2.00-1.80 (m, 4H),1.12- 1.00 (m, 9H). 857

548 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.30 (s, 1H), 8.18 (d, 1H, J= 1.5 Hz), 7.91 (d, 1H, J = 5.5 Hz), 7.80 (d, 2H, J = 8.5 Hz), 7.40 (d,2H, J = 8.5 Hz), 7.04 (d, 1H, J = 1.5 Hz), 5.99 (d, 1H, J = 5.5 Hz),5.34 (quintet6, 1H, J = 5.5 Hz), 4.79 (t, 2H, J = 7.0 Hz), 4.53 (dd, 2H,d, 2H, J = 7.0, 5.5 Hz), 3.80-3.65 (m, 2H), 3.65-3.50 (m, 2H), 3.50-3.40(m, 4H), 3.06 (q, 2H, J = 6.5 Hz), 2.90-2.80 (m, 1H), 2.80-2.70 (m, 2H),2.68-2.61 (m, 2H), 2.03-2.00 (m, 2H), 1.98- 1.92 (m, 2H), 1.09-1.05 (m,9H). 858

548 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.27 (d, 1H, J = 1.2 Hz), 8.16 (s, 1H), 7.92 (d, 1H, J = 5.6 Hz),7.91-7.88 (m, 1H), 7.78 (dd, 1H, J = 8.4, 2.4 Hz), 7.17 (d, 1H, J = 1.6Hz), 6.30 (d, 1H, J = 7.6 Hz), 5.99 (d, 1H, J = 5.6 Hz), 4.54 (t, 2H, J= 6.4 Hz), 4.43 (t, 2H, J = 6.4 Hz), 3.84-3.72 (m, 1H), 3.56-3.49 (m,4H), 3.48-3.43 (m, 4H), 3.44- 3.40 (m, 1H), 3.06 (q, 2H, J = 6.8 Hz),2.56- 2.51 (m, 2H), 2.22-2.12 (m, 2H), 2.06-1.86 (m, 4H), 1.08 (d, 6H, J= 6.4 Hz), 1.06 (t, 3H, J = 6.8 Hz). 859

552 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.40 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.6 Hz), 6.54 (t, 1H, J = 75.6 Hz), 5.99 (d, 1H, J= 5.6 Hz), 3.92 (m, 2H), 3.83 (s, 2H), 3.71 (m, 2H), 3.57-3.50 (m, 2H),3.50-3.43 (m, 2H), 2.60-2.57 (m, 3H), 2.30- 2.25 (m, 2H), 2.15-2.11 (m,2H), 2.14-1.99 (m, 1H), 1.88-1.83 (m, 2H), 0.90 (d, 6H, J = 6.8 Hz),0.79-0.77 (m, 4H). 860

552 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.6 Hz), 7.94- 7.90 (m, 2H), 7.79 (dd, 1H, J = 8.4, 2.4Hz), 7.17 (d, 1H, J = 2.0 Hz), 6.31 (d, 1H, J = 7.6 Hz), 6.00 (d, 1H, J= 5.6 Hz), 4.56-4.32 (m, 2H), 3.82-3.76 (m, 1H), 3.55-3.50 (m, 4H),3.48-3.43 (m, 4H), 3.08 (q, 2H, J = 7.2 Hz), 2.93-2.84 (m, 1H),2.71-2.63 (m, 4H), 2.03- 1.95 (m, 2H), 1.95-1.85 (m, 2H), 1.09-1.06 (m,9H), 1.18 (d, 3H, J = 5.6 Hz). 861

552 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.60 (d, 1H, J = 1.6 Hz),8.28 (d, 1H, J = 1.6 Hz), 8.17 (s, 1H), 7.95-7.91 (m, 2H), 7.81-7.77 (m,1H), 7.18 (d, 1H, J = 1.6 Hz), 6.31 (d, 1H, J = 7.6 Hz), 6.00 (d, 1H, J= 5.6 Hz), 4.95-4.78 (m, 1H), 3.82-3.76 (m, 1H), 3.55-3.51 (m, 4H),3.48-3.45 (m, 4H), 3.07 (q, 2H, J = 7.2 Hz), 2.80-2.65 (m, 2H),2.64-2.50 (m, 2H), 2.50- 2.45 (m, 2H), 2.08-1.93 (m, 4H), 1.27 (dd, 2H,J = 23.6 Hz, J = 6.4 Hz), 1.10-1.06 (m, 9H). 862

552 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.60 (d, 1H, J = 1.6 Hz),8.28 (d, 1H, J = 1.6 Hz), 8.16 (s, 1H), 7.95-7.91 (m, 2H), 7.81-7.77 (m,1H), 7.18 (d, 1H, J = 1.6 Hz), 6.31 (d, 1H, J = 7.6 Hz), 6.00 (d, 1H, J= 5.6 Hz), 4.97-4.78 (m, 1H), 3.82-3.76 (m, 1H), 3.55-3.51 (m, 4H),3.48-3.45 (m, 4H), 3.08 (q, 2H, J = 7.2 Hz), 2.80-2.65 (m, 2H),2.64-2.50 (m, 2H), 2.50- 2.43 (m, 2H), 1.99-1.93 (m, 4H), 1.27 (dd, 2H,J = 23.6 Hz, J = 6.4 Hz), 1.10-1.06 (m, 9H). 863

553 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.30 (d, 1H, J = 2.0 Hz), 8.16 (s, 1H), 7.96-7.92 (m, 2H), 7.78 (dd, 1H,J = 8.4, 2.0 Hz), 7.19 (d, 1H, J = 1.6 Hz), 6.01 (d, 1H, J = 5.2 Hz),5.34 (quintet, 1H, J = 5.2 Hz), 4.80 (t, 2H, J = 7.2 Hz), 4.55 (dd, 2H,J = 7.2, 5.2 Hz), 4.60-4.41 (m, 2H), 3.73-3.68 (m, 2H), 3.68-3.60 (m,2H), 3.55-3.50 (m, 4H), 3.10- 2.95 (m, 1H), 2.93 (s, 3H), 2.85-2.70 (m,4H), 2.10-2.00 (m, 2H), 2.00-1.92 (m, 2H), 1.06 (d, 3H, J = 6.4 Hz). 864

553 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.28 (s, 1H), 7.94-7.91 (m, 2H), 7.80-7.77 (m, 1H), 7.18 (s, 1H), 6.00(d, 1H, J = 5.2 Hz), 5.01-4.92 (m, 1H), 4.71-4.38 (m, 2H), 3.63-3.62 (m,4H), 3.50-3.49 (m, 4H), 3.08 (q, 2H, J = 6.8 Hz), 2.70-2.54 (m, 4H),2.44-2.33 (m, m1H), 2.01-1.98 (m, 2H), 1.91- 1.85 (m, 2H), 1.22 (d, 3H,J = 6.4 Hz), 1.08 (t, 3H, J = 6.8 Hz), 1.00 (d, 3H, J = 6.8 Hz). 865

553 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.4 Hz),8.28 (d, 1H, J = 1.6 Hz), 7.95- 7.91 (m, 2H), 7.80-7.77 (m, 1H), 7.18(d, 1H, J = 1.2 Hz), 6.00 (d, 1H, J = 5.2 Hz), 5.00-4.81 (m, 1H),4.28-4.06 (m, 2H), 3.65-3.64 (m, 4H), 3.52-3.50 (m, 4H), 3.08 (q, 2H, J= 6.8 Hz), 2.73-2.61 (m, 5H), 2.03-1.91 (m, 4H), 1.31 (dd, 3H, J = 24.0,6.8 Hz), 1.07 (t, 3H, J = 6.8 Hz), 0.99 (d, 6H, J = 6.4 Hz). 866

553 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.28 (s, 1H), 7.94-7.91 (m, 2H), 7.80-7.77 (m, 1H), 7.18 (s, 1H), 6.00(d, 1H, J = 5.2 Hz), 5.01-4.92 (m, 1H), 4.61-4.38 (m, 2H), 3.63-3.62 (m,4H), 3.50-3.49 (m, 4H), 3.08 (q, 2H, J = 6.8 Hz), 2.70-2.54 (m, 4H),2.44-2.33 (m, 1H), 2.01-1.98 (m, 2H), 1.91- 1.85 (m, 2H), 1.22 (d, 3H, J= 6.4 Hz), 1.08 (t, 3H, J = 6.8 Hz), 1.00 (d, 3H, J = 6.8 Hz). 867

553 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.4 Hz),8.28 (d, 1H, J = 1.6 Hz), 7.95- 7.91 (m, 2H), 7.80-7.77 (m, 1H), 7.18(d, 1H, J = 1.2 Hz), 6.00 (d, 1H, J = 5.2 Hz), 5.00-4.81 (m, 1H),4.28-4.06 (m, 2H), 3.65-3.64 (m, 4H), 3.52-3.50 (m, 4H), 3.08 (q, 2H, J= 6.8 Hz), 2.73-2.61 (m, 5H), 2.03-1.91 (m, 4H), 1.31 (dd, 3H, J = 24.0,6.8 Hz), 1.07 (t, 3H, J = 6.8 Hz), 0.99 (d, 6H, J = 6.4 Hz). 868

555 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 2.0 Hz),7.90 (d, 1H, J = 5.2 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.6 Hz), 6.49 (t, 1H, J = 75.2 Hz), 6.32 (s, 1H),5.99 (d, 1H, J = 5.6 Hz), 4.35-4.29 (m, 1H), 3.82-3.74 (m, 1H), 3.53-3.51 (m, 4H), 3.46-3.43 (m, 4H), 2.89-2.80 (m, 2H), 2.80-2.74 (m, 2H),2.31 (t, 2H, J = 10.8 Hz), 2.12-2.10 (m, 1H), 1.68-1.64 (m, 1H), 1.09(d, 6H, J = 6.4 Hz), 0.98-0.94 (m, 6H). 869

555 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.16 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.6 Hz), 6.49 (t, 1H, J = 76.4 Hz), 6.32-6.30 (m,1H), 5.98 (d, 1H, J = 5.2 Hz), 4.32 (td, 1H, J = 10.4, 4.4 Hz),3.82-3.74 (m, 1H), 3.53-3.51 (m, 4H), 3.46-3.43 (m, 4H), 2.89-2.80 (m,2H), 2.80-2.74 (m, 2H), 2.31 (t, 2H, J = 10.8 Hz), 2.12-2.10 (m, 1H),1.68-1.64 (m, 1H), 1.09 (d, 6H, J = 6.4 Hz), 0.98-0.94 (m, 6H). 870

556 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.6 Hz), 7.96- 7.90 (m, 2H), 7.78 (dd, 1H, J = 8.0, 2.4Hz), 7.18 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.58-4.50 (m,2H), 4.48-4.40 (m, 2H), 3.72-3.60 (m, 3H), 3.58-3.52 (m, 2H), 3.50- 3.38(m, 5H), 3.30-3.20 (m, 1H), 2.91 (s, 3H), 2.68-2.57 (m, 2H), 2.56-2.50(m, 4H), 2.20- 2.10 (m, 2H), 2.05-1.85 (m, 4H). 871

556 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.30 (d, 1H, J = 2.0 Hz), 8.17 (s, 1H), 7.96-7.91 (m, 2H), 7.80 (dd, 1H,J = 2.5 Hz, 8.0 Hz), 7.19 (d, 1H, J = 1.5 Hz), 5.99 (d, 1H, J = 5.5 Hz),3.75-3.60 (m, 3H), 3.60- 3.52 (m, 2H), 3.52-3.40 (m, 4H), 3.35-3.20 (m,3H), 3.15-3.05 (m, 2H), 3.00-2.88 (m, 1H), 2.88-2.75 (m, 2H), 2.75-2.55(m, 4H), 2.15- 1.90 (m, 4H), 1.15-1.00 (m, 9H). 872

557 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.0 Hz), 7.95- 7.91 (m, 2H), 7.78 (dd, 1H, J = 8.0, 2.0Hz), 7.19 (d, 1H, J = 1.0 Hz), 6.28 (tt, 1H, J = 54.5, 3.5 Hz), 6.01 (d,1H, J = 5.0 Hz), 4.35 (td, 2H, J = 15.5, 3.5 Hz), 3.66-3.65 (m, 4H),3.52-3.49 (m, 4H), 3.08 (q, 2H, J = 6.5 Hz), 2.70-2.67 (m, 1H),2.62-2.60 (m, 2H), 2.53-2.51 (m, 2H), 2.01-1.98 (m, 2H), 1.91-1.87 (m,2H), 1.08 (t, 3H, J = 6.5 Hz), 1.00 (d, 6H, J = 6.5 Hz). 873

559 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.24 (d, 1H, J = 1.6 Hz),8.00 (d, 1H, J = 5.2 Hz), 7.92 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H, J = 1.6Hz), 7.75 (dd, 1H, J = 8.4, 2.0 Hz), 7.12 (d, 1H, J = 2.0 Hz), 6.07 (d,1H, J = 5.6 Hz), 5.34 (quintet, 1H, J = 5.2 Hz), 4.79 (t, 2H, J = 7.2Hz), 4.53 (dd, 2H, J = 7.2, 5.2 Hz), 3.69-3.67 (m, 2H), 3.59-3.57 (m,2H), 3.53-3.51 (m, 4H), 2.91 (s, 3H), 2.72-2.68 (m, 1H), 2.63-2.59 (m,2H), 2.48-2.44 (m, 2H), 2.01-1.97 (m, 2H), 1.91- 1.85 (m, 2H), 1.01 (d,6H, J = 6.4 Hz). 874

563 1H-NMR (H NMR (500 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.00 (d, J =1.8 Hz, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.46(d, J = 8.1 Hz, 2H), 6.92 (d, J = 1.9 Hz, 1H), 6.03 (d, J = 5.5 Hz, 1H),4.99-4.92 (m, 1H), 3.88- 3.63 (m, 8H), 3.55 (s, 5H), 3.44 (d, J = 15.6Hz, 1H), 3.12 (d, J = 53.8 Hz, 2H), 2.97-2.67 (m, 2H), 2.23 (s, 2H),1.35 (d, J = 6.6 Hz, 6H). 875

563 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.6 Hz), 7.94 (d, 1H, J = 5.2 Hz), 7.93-7.90 (m, 1H),7.79 (dd, 1H, J = 8.4, 2.4 Hz), 7.18 (d, 1H, J = 2.0 Hz), 6.00 (d, 1H, J= 5.2 Hz), 5.33 (quintet, 1H, J = 5.2 Hz), 4.78 (t, 2H, J = 7.2 Hz),4.60- 4.50 (m, 4H), 4.44 (t, 2H, J = 5.6 Hz), 3.73- 3.66 (m, 2H),3.66-3.58 (m, 2H), 3.54-3.47 (m, 4H), 3.46-3.36 (m, 1H), 3.06 (q, 2H, J= 6.8 Hz), 2.58-2.51 (m, 2H), 2.24-2.10 (m, 2H), 2.06-1.86 (m, 4H), 1.07(t, 3H, J = 6.8 Hz). 876

563 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.5 Hz), 7.94- 7.91 (m, 2H), 7.78 (dd, 1H, J = 8.0, 2.5Hz), 7.18 (d, 1H, J = 2.0 Hz), 6.00 (d, 1H, J = 6.0 Hz), 5.19-5.18 (m,1H), 3.82-3.79 (m, 2H), 3.76-3.71 (m, 2H), 3.62-3.60 (m, 4H), 3.50- 3.48(m, 4H), 3.08 (q, 2H, J = 7.0 Hz), 2.70- 2.68 (m, 1H), 2.62-2.60 (m,2H), 2.54-2.51 (m, 2H), 2.16-2.12 (m, 1H), 2.01-1.92 (m, 3H), 1.92-1.86(m, 2H), 1.08 (t, 3H, J = 7.0 Hz), 1.00 (d, 6H, J = 7.0 Hz). 877

563 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.5 Hz), 7.94- 7.91 (m, 2H), 7.78 (dd, 1H, J = 8.0, 2.5Hz), 7.18 (d, 1H, J = 2.0 Hz), 6.00 (d, 1H, J = 6.0 Hz), 5.19-5.18 (m,1H), 3.82-3.79 (m, 2H), 3.76-3.71 (m, 2H), 3.62-3.60 (m, 4H), 2.50- 3.48(m, 4H), 3.08 (q, 2H, J = 7.0 Hz), 2.70- 2.68 (m, 1H), 2.62-2.60 (m,2H), 2.54-2.51 (m, 2H), 2.16-2.12 (m, 1H), 2.01-1.92 (m, 3H), 1.92-1.86(m, 2H), 1.08 (t, 3H, J = 7.0 Hz), 1.00 (d, 6H, J = 7.0 Hz). 878

563 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (s, 1H), 8.29 (s, 1H),7.94 (d, 1H, J = 5.2 Hz), 7.93-7.91 (m, 1H), 7.79 (d, 1H, J = 8.0 Hz),7.18 (s, 1H), 6.00 (d, 1H, J = 5.2 Hz), 4.66 (d, 2H, J = 7.2 Hz), 4.42(d, 2H, J = 7.2 Hz), 3.66- 3.63 (m, 2H), 3.63-3.58 (m, 2H), 3.51-3.48(m, 4H), 3.08 (q, 2H, J = 7.2 Hz), 2.80-2.70 (m, 2H), 2.70-2.60 (m, 2H),2.02-1.99 (m, 2H), 1.92-1.90 (m, 2H), 1.67 (s, 3H), 1.08 (t, 3H, J = 7.2Hz), 1.01-0.99 (m, 6H). 879

563 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.61 (s, 1H), 8.31 (d, 1H, J= 1.0 Hz), 7.98-7.94 (m, 2H), 7.81-7.78 (m, 1H), 7.21-7.18 (m, 1H),6.02-6.00 (m, 1H), 5.40-5.30 (m, 0.25H), 5.05- 4.95 (m, 0.25H),4.95-4.85 (m, 0.75H), 4.80- 4.70 (m, 1H), 4.65-4.58 (m, 0.75H),4.45-4.30 (m, 1H), 3.75-3.40 (br., 2H), 3.70-3.62 (m, 2H), 3.62-3.55 (m,2H), 3.55-3.48 (m, 4H), 3.30-3.25 (m, 1H), 3.11 (q, 2H, J = 7.0 Hz),2.45-2.10 (m, 4H), 1.38 (d, 6H, J = 7.0 Hz), 1.30 (d, 3H, J = 6.0 Hz),1.30-1.20 (m, 2H), 1.11 (t, 3H, J = 7.0 Hz). 880

567 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 1.6 Hz),8.29 (d, 1H, J = 1.6 Hz), 7.95- 7.92 (m, 2H), 7.80 (dd, 1H, J = 8.0, 2.4Hz), 7.18 (d, 1H, J = 1.6 Hz), 6.01 (d, 1H, J = 5.6 Hz), 5.34 (quintet,1H, J = 5.2 Hz), 4.97-4.90 (m, 1H), 4.79 (t, 2H, J = 7.2 Hz), 4.53 (dd,2H, J = 7.2, 5.2 Hz), 3.73-3.65 (m, 2H), 3.65-3.59 (m, 2H), 3.52-3.50(m, 4H), 3.33-3.31 (m, 2H), 2.50-2.49 (m, 2H), 1.91-1.75 (m, 4H), 1.27(dd, 3H, J = 24.0, 6.4 Hz), 1.08 (t, 3H, J = 6.8 Hz). 881

567 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.59 (s, 1H), J = 1.6 Hz),8.30 (d, 1H, J = 1.6 Hz), 8.22 (s, 1H), 7.96-7.91 (m, 2H), 7.79 (dd, 1H,J = 8.4, 2.4 Hz), 7.19 (d, 1H, J = 1.2 Hz), 6.01 (d, 1H, J = 5.6 Hz),5.34 (quintet, 1H, J = 5.6 Hz), 4.79 (t, 2H, J = 7.2 Hz), 4.54 (dd, 2H,J = 7.2, \5.6 Hz), 4.50-4.33 (m, 2H), 3.75-3.65 (m, 2H), 3.65-3.55 (m,2H), 3.55-3.48 (m, 4H), 3.08 (q, 2H, J = 7.2 Hz), 2.95-2.85 (m, 1H),2.73-2.65 (m, 4H), 2.05-1.95 (m, 2H), 1.95-1.85 (m, 2H), 1.08 (t, 3H, J= 7.2 Hz), 1.26 (d, 3H, J = 6.8 Hz). 882

567 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.60 (d, 1H, J = 2.0 Hz),8.30 (d, 1H, J = 1.6 Hz), 8.18 (s, 1H), 7.96-7.91 (m, 2H), 7.79 (dd, 1H,J = 8.0, 2.4 Hz), 7.19 (d, 1H, J = 1.2 Hz), 6.01 (d, 1H, J = 5.6 Hz),5.33 (quintet, 1H, J = 5.2 Hz), 4.95-4.77 (m, 1H), 4.80 (t, 2H, J = 7.2Hz), 4.54 (dd, 2H, J = 7.2, 5.2 Hz), 3.72-3.65 (m, 2H), 2.65-2.57 (m,2H), 3.57-3.48 (m, 4H), 3.07 (q, 2H, J = 7.2 Hz), 2.80-2.71 (m, 2H),2.70-2.50 (m, 2H), 2.50-2.48 (m, 2H), 2.02- 1.90 (m, 4H), 1.27 (dd, 3H,J = 23.6 Hz, 6.4 Hz), 1.08 (t, 3H, J = 7.2 Hz). 883

568 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.6 Hz), 6.69 (d, 1H, J = 76.4 Hz), 5.98 (d, 1H, J= 5.6 Hz), 4.00-3.85 (m, 3H), 3.82-3.65 (m, 3H), 3.55-3.50 (m, 2H),3.50-3.45 (m, 2H), 2.89 (s, 3H), 2.88-2.82 (m, 1H), 2.75-2.53 (m, 4H),2.08-1.95 (m, 3H), 1.92-1.85 (m, 2H), 1.01 (d, 3H, J = 6.8 Hz),0.82-.072 (m, 4H). 884

568 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.05 (d, 1H, J = 1.6 Hz), 6.69 (d, 1H, J = 76.4 Hz), 5.98 (d, 1H, J= 5.6 Hz), 4.00-3.85 (m, 3H), 3.82-3.65 (m, 3H), 3.55-3.50 (m, 2H),3.50-3.45 (m, 2H), 2.89 (s, 3H), 2.88-2.82 (m, 1H), 2.75-2.53 (m, 4H),2.08-1.95 (m, 3H), 1.92-1.85 (m, 2H), 1.01 (d, 3H, J = 6.8 Hz),0.82-.072 (m, 4H). 885

569 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (s, 1H), 8.29 (s, 1H),8.27 (s, 0.4H, HCOOH), 7.93 (d, 1H, J = 4.8 Hz), 7.92 (d, 1H, J = 8.4Hz), 7.78 (d, 1H, J = 8.0 Hz), 7.21 (s, 1H), 6.68 (t, 1H, J = 76.0 Hz),5.98 (d, 1H, J = 5.2 Hz), 3.93-3.89 (m, 3H), 3.76-3.72 (m, 3H),3.57-3.51 (m, 4H), 2.92 (s, 3H), 2.89-2.84 (m, 1H), 2.67-2.61 (m, 4H),2.03-2.00 (m, 3H), 1.89-1.86 (m, 2H), 1.01 (d, 3H, J = 6.8 Hz),0.78-0.75 (m, 4H). 886

569 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.30 (d, 1H, J = 1.5 Hz), 7.94- 7.92 (m, 2H), 7.77 (dd, 1H, J = 8.5, 2.0Hz), 7.21 (d, 1H, J = 1.5 Hz), 6.69 (t, 1H, J = 76.0 Hz), 5.99 (d, 1H, J= 5.5 Hz), 3.94-3.89 (m, 3H), 3.76-3.72 (m, 3H), 3.58-3.54 (m, 2H),3.54-3.50 (m, 2H), 2.92 (s, 3H), 2.87-2.86 (m, 1H), 2.65-2.62 (m, 1H),2.61-2.57 (m, 3H), 2.03-2.01 (m, 3H), 1.90-1.89 (m, 2H), 1.02 (d, 3H, J= 6.5 Hz), 0.80-0.75 (m, 4H). 887

569 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.27 (s, 1H), 8.17 (d, 1H, J= 2.0 Hz), 7.90 (d, 1H, J = 5.5 Hz), 7.76 (d, 2H, J = 8.5 Hz), 7.40 (d,2H, J = 8.5 Hz), 7.01 (d, 1H, J = 2.0 Hz), 6.53 (t, 1H, J = 76.0 Hz),6.31 (d, 1H, J = 7.5 Hz), 5.98 (d, 1H, J = 5.0 Hz), 3.83 (s, 2H),3.81-3.76 (m, 1H), 3.54-3.50 (m, 4H), 3.48-3.42 (m, 4H), 2.65-2.60 (m,3H), 2.32-2.28 (m, 2H), 2.15- 2.13 (m, 2H), 1.89-1.85 (m, 2H), 1.07 (d,6H, J = 7.0 Hz), 0.92 (d, 6H, J = 6.5 Hz). 888

570 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.5 Hz),7.91 (d, 1H, J = 6.0 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.34 (d, 2H, J = 8.0Hz), 7.03 (d, 1H, J = 1.5 Hz), 6.49 (t, 1H, J = 76.5 Hz), 5.99 (d, 1H, J= 5.0 Hz), 5.34 (quintet, 1H, J = 6.5 Hz), 4.79 (t, 2H, J = 7.0 Hz),4.53 (dd, 2H, J = 7.5, 5.5 Hz), 4.35-4.29 (m, 1H), 3.71-3.69 (m, 2H),3.61-3.59 (m, 2H), 3.50- 3.48 (m, 4H), 2.89-2.80 (m, 2H), 2.80-2.72 (m,2H), 2.31 (t, 2H, J = 11.0 Hz), 2.12-2.10 (m, 1H), 1.68-1.62 (m, 1H),1.51-1.47 (m, 1H), 0.97-0.94 (m, 6H). 889

570 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.6 Hz),7.91 (d, 1H, J = 5.2 Hz), 7.75 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.6 Hz6.49 (t, 1H, J = 76.4 Hz), 5.99 (d, 1H, J =5.6 Hz), 5.34 (quintet, 1H, J = 5.6 Hz), 4.79 (t, 2H, J = 7.2 Hz), 4.53(dd, 2H, J = 8.0, 5.6 Hz), 4.35-4.29 (m, 1H), 3.70-3.65 (m, 2H),3.6-3.59 (m, 2H), 3.50- 3.48 (m, 4H), 2.86-2.79 (m, 2H), 2.79-2.72 (m,2H), 2.31 (t, 2H, J = 11.2 Hz), 2.12-2.10 (m, 1H), 1.68-1.62 (m, 1H),0.98-0.94 (m, 6H). 890

570 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.60 (d, 1H, J = 1.6 Hz),8.30 (d, 1H, J = 1.6 Hz), 8.17 (s, 1H), 7.95-7.91 (m, 2H), 7.81-7.78 (m,1H), 7.19 (d, 1H, J = 1.6 Hz), 5.98 (d, 1H, J = 5.6 Hz), 4.55 (t, 2H, J= 6.4 Hz), 4.44 (t, 2H, J = 6.4 Hz), 3.71-3.65 (m, 3H), 3.57-3.54 (m,2H), 3.49-3.46 (m, 4H), 3.45-3.42 (m, 1H), 3.31- 3.26 (m, 1H), 3.07 (q,2H, J = 7.2 Hz), 2.67- 2.59 (m, 2H), 2.54-2.51 (m, 2H), 2.50-21.48 (m,2H), 2.21-2.15 (m, 2H), 2.03-1.90 (m, 4H), 1.08 (t, 3H, J = 7.2 Hz). 891

584 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.18 (s, 1H), 7.92 (d, 1H, J= 5.5 Hz), 7.76 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.02 (s,1H), 6.53 (t, 1H, J = 76.0 Hz), 6.00 (d, 1H, J = 5.5 Hz), 5.33 (quintet,1H, J = 5.0 Hz), 4.79 (t, 2H, J = 7.0 Hz), 4.53 (dd, 2H, J = 7.0, 5.0Hz), 3.83 (s, 2H), 3.75-3.70 (m, 2H), 3.70-3.65 (m, 2H), 3.52-3.47 (m,4H), 2.60-2.56 (m, 3H), 2.32-2.28 (m, 2H), 2.15-2.13 (m, 2H), 1.90- 1.87(m, 2H), 0.91 (d, 6H, J = 7.0 Hz). 892

585 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.2 Hz), 6.68 (t, 1H, J = 76.4 Hz), 6.30 (d, 1H, J= 7.6 Hz), 5.99 (d, 1H, J = 5.2 Hz), 3.91-3.87 (m, 1H), 3.80-3.73 (m,2H), 3.53-3.48 (m, 4H), 3.46-3.41 (m, 4H), 2.89 (s, 3H), 2.88-2.83 (m,1H), 2.75-2.53 (m, 4H), 2.03-1.93 (m, 2H), 1.90-1.82 (m, 2H), 1.06 (d,6H, J = 8.4 Hz), 1.01 (d, 3H, J = 6.4 Hz). 893

585 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.17 (d, 1H, J = 1.6 Hz),7.90 (d, 1H, J = 5.6 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.01 (d, 1H, J = 1.2 Hz), 6.68 (t, 1H, J = 76.4 Hz), 6.30 (d, 1H, J= 7.6 Hz), 5.99 (d, 1H, J = 5.2 Hz), 3.91-3.87 (m, 1H), 3.80-3.73 (m,2H), 3.53-3.48 (m, 4H), 3.46-3.41 (m, 4H), 2.89 (s, 3H), 2.88-2.83 (m,1H), 2.75-2.53 (m, 4H), 2.03-1.93 (m, 2H), 1.90-1.82 (m, 2H), 1.06 (d,6H, J = 8.4 Hz), 1.01 (d, 3H, J = 6.4 Hz). 894

586 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 1.6 Hz),8.28 (d, 1H, J = 1.6 Hz), 7.93- 7.91 (m, 2H), 7.77 (dd, 1H, J = 8.4, 2.0Hz), 7.17 (d, 1H, J = 1.6 Hz), 6.68 (t, 1H, J = 76.4 Hz), 6.30 (d, 1H, J= 7.6 Hz), 5.99 (d, 1H, J = 5.2 Hz), 3.93-3.89 (m, 1H), 3.80-3.77 (m,1H), 3.77-3.72 (m, 1H), 3.54-3.53 (m, 4H), 3.47- 3.46 (m, 4H), 2.92 (s,3H), 2.89-2.86 (m, 1H), 2.67-2.62 (m, 1H), 2.61-2.56 (m, 3H), 2.04- 2.01(m, 2H), 1.89-1.86 (m, 2H), 1.08 (d, 6H, J = 6.8 Hz), 1.02 (d, 3H, J =6.4 Hz). 895

590 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.59 (d, 1H, J = 2.0 Hz),8.28 (d, 1H, J = 1.5 Hz), 7.94 (d, 1H, J = 5.5 Hz), 7.91 (d, 1H, J = 8.0Hz), 7.78 (dd, 1H, J = 8.0, 2.0 Hz), 7.18 (d, 1H, J = 1.5 Hz), 6.01 (d,1H, J = 5.5 Hz), 5.10-5.08 (m, 1H), 4.43 (dd, 1H, J = 9.5, 7.0 Hz), 4.14(dd, 1H, J = 10.5, 7.0 Hz), 4.09 (dd, 1H, J = 9.5, 4.0 Hz), 3.78 (dd,1H, J = 10.5, 4.0 Hz), 3.71- 3.65 (m, 2H), 3.65-3.59 (m, 2H), 3.52-3.51(m, 4H), 3.08 (q, 2H, J = 7.0 Hz), 2.70-2.68 (m, 1H), 2.62-2.60 (m, 2H),2.54-2.51 (m, 2H), 2.01-1.98 (m, 2H), 1.91-1.89 (m, 2H), 1.78 (s, 3H),1.08 (t, 3H, J = 7.0 Hz), 1.00 (d, 6H, J = 7.0 Hz). 896

600 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.2 Hz),7.92 (d, 1H, J = 5.2 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.6 Hz), 6.69 (d, 1H, J = 76.4 Hz), 6.00 (d, 1H, J= 5.2 Hz), 5.34 (quintet, 1H, J = 5.6 Hz), 4.79 (t, 2H, J = 6.8 Hz),4.53 (dd, 2H, J = 6.8, 5.6 Hz), 3.92-3.87 (m, 1H), 3.77-3.72 (m, 1H),3.75-3.69 (m, 2H), 3.69- 3.66 (m, 2H), 3.62-3.58 (m, 4H), 2.89 (s, 3H),2.88-2.83 (m, 1H), 2.75-2.55 (m, 4H), 2.03- 1.96 (m, 2H), 1.90-1.81 (m,2H), 1.01 (d, 3H, J = 6.4 Hz). 897

600 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.18 (d, 1H, J = 1.2 Hz),7.92 (d, 1H, J = 5.2 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4Hz), 7.03 (d, 1H, J = 1.6 Hz), 6.69 (d, 1H, J = 76.4 Hz), 6.00 (d, 1H, J= 5.2 Hz), 5.34 (quintet, 1H, J = 5.6 Hz), 4.79 (t, 2H, J = 6.8 Hz),4.53 (dd, 2H, J = 6.8, 5.6 Hz), 3.92-3.87 (m, 1H), 3.77-3.72 (m, 1H),3.75-3.69 (m, 2H), 3.69- 3.66 (m, 2H), 3.62-3.58 (m, 4H), 2.89 (s, 3H),2.88-2.83 (m, 1H), 2.75-2.55 (m, 4H), 2.03- 1.96 (m, 2H), 1.90-1.81 (m,2H), 1.01 (d, 3H, J = 6.4 Hz). 898

601 1H-NMR (H-NMR (400 MHz, 6d-DMSO) δ ppm 8.58 (s, 1H), 8.29 (s, 1H),8.27 (s, 0.4H, HCOOH), 7.94 (d, 1H, J = 5.6 Hz), 7.92 (d, 1H, J = 4.4Hz), 7.78 (d, 1H, J = 4.4 Hz), 7.19 (s, 1H), 6.69 (t, 1H, J = 76.4 Hz),6.01 (d, 1H, J = 5.2 Hz), 5.35-5.31 (m, 1H), 4.81-4.77 (m, 2H),4.55-4.51 (m, 2H), 3.93-3.89 (m, 1H), 3.78- 3.68 (m, 8H), 2.92 (s, 3H),2.89-2.84 (m, 2H), 2.70-2.58 (m, 4H), 2.03-2.00 (m, 2H), 1.89- 1.78 (m,2H), 1.01 (d, 3H, J = 6.4 Hz). 899

601 1H-NMR (H-NMR (500 MHz, 6d-DMSO) δ ppm 8.58 (d, 1H, J = 2.0 Hz),8.29 (d, 1H, J = 1.5 Hz), 7.95- 7.92 (m, 2H), 7.78 (dd, 1H, J = 8.5, 2.5Hz), 7.19 (d, 1H, J = 1.5 Hz), 6.69 (t, 1H, J = 76.0 Hz), 6.01 (d, 1H, J= 5.5 Hz), 5.34 (quintet, 1H, J = 5.5 Hz), 4.79 (t, 2H, J = 7.5 Hz),4.53 (dd, 2H, J = 7.5, 5.5 Hz), 3.91-3.89 (m, 1H), 3.76-3.74 (m, 1H),3.75-3.70 (m, 2H), 3.62- 3.57 (m, 2H), 3.51-3.49 (m, 4H), 2.92 (s, 3H),2.87-2.86 (m, 1H), 2.70-2.67 (m, 1H), 2.67- 2.61 (m, 3H), 2.03-2.01 (m,2H), 1.90-1.89 (m, 2H), 1.02 (d, 3H, J = 6.5 Hz).

In another aspect, the present disclosure features a method of treatingor ameliorating fibrodysplasia ossificans progressiva in a subject,comprising administering to the subject a pharmaceutically effectiveamount of a compound described herein (e.g., a compound in Table 1) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof.

In another aspect, the present disclosure features a method of treatingor ameliorating diffuse intrinsic pontine glioma in a subject,comprising administering to the subject a pharmaceutically effectiveamount of a compound described herein (e.g., a compound in Table 1) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof.

In another aspect, the present disclosure features a method ofinhibiting aberrant ALK2 activity in a subject, comprising administeringto the subject a therapeutically effective amount of a compounddescribed herein (e.g., a compound in Table 1) or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition thereof.

Pharmaceutically acceptable salts of these compounds are alsocontemplated for the uses described herein.

“Pharmaceutically acceptable salt” refers to any salt of a compound ofthe disclosure which retains its biological properties and which is nottoxic or otherwise undesirable for pharmaceutical use. Pharmaceuticallyacceptable salts may be derived from a variety of organic and inorganiccounter-ions. Such salts include one or more of: (1) acid addition saltsformed with organic or inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic,trifluoroacetic, trichloroacetic, propionic, hexanoic,cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic,succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric,benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic,phthalic, lauric, methanesulfonic, ethanesulfonic,1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic,4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic,camphoric, camphorsulfonic,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic, glucoheptonic,3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric,gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic,cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2)salts formed when an acidic proton present in the parent compound either(a) is replaced by a metal ion, e.g., an alkali metal ion, an alkalineearth ion or an aluminum ion, or alkali metal or alkaline earth metalhydroxides, such as sodium, potassium, calcium, magnesium, aluminum,lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with anorganic base, such as aliphatic, alicyclic, or aromatic organic amines,such as ammonia, methylamine, dimethylamine, diethylamine, picoline,ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylene-diamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, and the like. Pharmaceutically acceptablesalts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium and the like, and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, besylate, acetate, maleate, oxalate and the like. Apharmaceutically acceptable salt according to the disclosure includes atleast one salt, and also may be mixtures of more than one salt.

Pharmaceutical Compositions

Pharmaceutical compositions of the disclosure comprise one or morecompounds of the disclosure and one or more pharmaceutically acceptablecarrier(s). The term “pharmaceutically acceptable carrier” refers to apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting any subject compositionor component thereof. Each carrier must be “acceptable” in the sense ofbeing compatible with the subject composition and its components and notinjurious to the patient. Some examples of materials which may serve aspharmaceutically acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The compositions of the disclosure may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally, or via an implanted reservoir. The term“parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. In an embodiment, the compositions of thedisclosure are administered orally, intraperitoneally or intravenously.Sterile injectable forms of the compositions of this disclosure may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tween, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this disclosure may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions, or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring, or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of thisdisclosure may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

The pharmaceutically acceptable compositions of this disclosure may alsobe administered topically, especially when the target of treatmentincludes areas or organs readily accessible by topical application,including diseases of the eye, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs. Topical application for the lower intestinal tract canbe effected in a rectal suppository formulation (see above) or in asuitable enema formulation. Topically-transdermal patches may also beused.

For topical applications, the pharmaceutically acceptable compositionsmay be formulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this disclosure include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutically acceptable compositions canbe formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The pharmaceutically acceptable compositions of this disclosure may alsobe administered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of the compounds of the present disclosure that may becombined with the carrier to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration, and other factors determined by the person administeringthe single dosage form.

Dosages

Toxicity and therapeutic efficacy of compounds of the disclosure,including pharmaceutically acceptable salts and deuterated variants, canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals. The LD₅₀ is the dose lethal to 50% of thepopulation. The ED₅₀ is the dose therapeutically effective in 50% of thepopulation. The dose ratio between toxic and therapeutic effects(LD₅₀/ED₅₀) is the therapeutic index. Compounds that exhibit largetherapeutic indexes are preferred. While compounds that exhibit toxicside effects may be used, care should be taken to design a deliverysystem that targets such compounds to the site of affected tissue inorder to minimize potential damage to uninfected cells and, thereby,reduce side effects.

Data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds may lie within a range of circulating concentrations thatinclude the ED₅₀ with little or no toxicity. The dosage may vary withinthis range depending upon the dosage form employed and the route ofadministration utilized. For any compound, the therapeutically effectivedose can be estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound that achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including but not limited to the activity of the specificcompound employed, the age, body weight, general health, sex, diet, timeof administration, rate of excretion, drug combination, and the judgmentof the treating physician and the severity of the particular diseasebeing treated. The amount of a compound of the present disclosure in thecomposition will also depend upon the particular compound in thecomposition.

Treatment

Mutations in ALK2 cause the kinase to be inappropriately active and areassociated with various diseases. The disclosure provides compounds thatinhibit a mutant ALK2 gene, e.g., a mutant ALK2 gene that results in theexpression of an ALK2 enzyme having an amino acid modification. Inanother aspect, the disclosure provides compounds that inhibit both wildtype (WT) ALK2 protein and mutant forms of ALK2 protein. For thepurposes of this disclosure, sequence information for ALK2 is found onthe National Center for Biological Information (NCBI) webpage(https://www.ncbi.nlm.nih.gov/) under ACVR1 activin A receptor type 1[Homo sapiens (human)]; Entrez Gene ID (NCBI): 90. It is also known as:FOP; ALK2; SKR1; TSRI; ACTRI; ACVR1A; ACVRLK2 said sequence informationis incorporated herein.

In an embodiment, the disclosure provides a method of inhibitingaberrant ALK2 activity in a subject comprising the step of administeringto the subject in need thereof a pharmaceutically effective amount of atleast one compound or pharmaceutical composition described herein. In anembodiment, the aberrant ALK2 activity is caused by a mutation in anALK2 gene that results in the expression of an ALK2 enzyme having anamino acid modification selected from one or more of L196P, PF197-8L,R202I, R206H, Q207E, R258S, R258G, G328A, G328V, G328W, G328E, G328R,G356D, and R375P. In an embodiment, the ALK2 enzyme has the amino acidmodification R206H.

Because of their activity against ALK2, the compounds described hereincan be used to treat a patient with a condition associated with aberrantALK2 activity. In an embodiment, the condition associated with aberrantALK2 activity is fibrodysplasia ossificans progressiva. FOP diagnosis isbased on the presence of congenital malformations of the great toes(hallux valgus) and the formation of fibrous nodules in soft tissues.The nodules may or may not transform into heterotopic bone. These softtissue lesions are often first noted in the head, neck back. ˜97% of FOPpatients have the same c.617G>A; R206H mutation in the ACVR1 (Alk2)gene. There is a genetic test available through the University ofPennsylvania (Kaplan et all, Pediatrics 2008, 121(5): e1295-e1300).

Other common congenital anomalies include malformations of the thumbs,short broad femoral necks, tibial osteochondromas and fused facet jointsof the cervical spine. The fused facet joints in the neck often causetoddlers to scoot on their buttocks rather than crawl. FOP is commonlymisdiagnosed (˜80%; cancer or fibromatosis) and patients are frequentlysubjected to inappropriate diagnostic procedures such as biopsies thatexacerbate disease and cause permanent disability.

In an embodiment, the present disclosure provides a method of treatingor ameliorating fibrodysplasia ossificans progressiva in a subject,comprising administering to the subject in need thereof apharmaceutically effective amount of a compound or pharmaceuticalcomposition described herein.

In an embodiment, the condition associated with aberrant ALK2 activityis fibrodysplasia ossificans progressiva (FOP) and the subject has amutation in an ALK2 gene that results in the expression of an ALK2enzyme having an amino acid modification selected from one or more ofL196P, PF197-8L, R202I, R206H, Q207E, R258S, R258G, G328A, G328W, G328E,G328R, G356D, and R375P. In one aspect of this embodiment, the ALK2enzyme has the amino acid modification R206H.

The present disclosure includes methods of identifying and/or diagnosingpatients for treatment with one or more of the compounds orpharmaceutical compositions described herein.

In an embodiment, the disclosure provides a method of detecting acondition associated with aberrant ALK2 activity e.g., FOB in a subject,wherein the method includes a. obtaining a sample e.g., plasma from thesubject e.g., a human patient; and b. detecting whether one or moremutations in an ALK2 gene as described herein are present in the sample.In another embodiment, the disclosure provides a method of diagnosing acondition associated with aberrant ALK2 activity in a subject, saidmethod comprising: a. obtaining a sample from the subject; b. detectingwhether one or more mutations in an ALK2 gene as described herein arepresent in the sample using a detection method described herein; and c.diagnosing the subject with the condition when the presence of the oneor more mutations is detected. Methods for detecting a mutation includebut are not limited to hybridization-based methods, amplification-basedmethods, microarray analysis, flow cytometry analysis, DNA sequencing,next-generation sequencing (NGS), primer extension, PCR, in situhybridization, dot blot, and Southern blot. In an embodiment, thepresent disclosure provides a method of diagnosing and treating acondition associated with aberrant ALK2 activity in a subject, saidmethod comprising a. obtaining a sample from a subject; b. detectingwhether one or more mutations in an ALK2 gene as described herein arepresent in the sample; diagnosing the subject with the condition whenthe one or more mutations in the sample are detected; and d.administering an effective amount of one or more of the compounds or apharmaceutical composition described herein to the diagnosed patient. Inan embodiment, the disclosure provides a method of treating a conditionassociated with aberrant ALK2 activity in a subject, said methodcomprising a. determining if, having determined if, or receivinginformation that the subject has one or more mutations in an ALK2 geneas described herein; b. identifying the subject as responsive to one ormore compounds or a pharmaceutical composition described herein; and c.administering an effective amount of the one or more compounds orpharmaceutical compositions to the subject.

In an embodiment, the condition associated with aberrant ALK2 activityis a brain tumor, e.g., glial tumor. In an embodiment, the glial tumoris diffuse intrinsic pontine glioma (DIPG). In an embodiment, thedisclosure provides a method of treating or ameliorating diffuseintrinsic pontine glioma in a subject, comprising administering to thesubject in need thereof a pharmaceutically effective amount of acompound or pharmaceutical composition described herein.

In an embodiment, the condition associated with aberrant ALK2 activityis diffuse intrinsic pontine glioma and the subject has a mutation in anALK2 gene that results in the expression of an ALK2 enzyme having anamino acid modification selected from one or more of R206H, G328V,G328W, G328E, and G356D. In one aspect of this embodiment, the ALK2enzyme has the amino acid modification R206H.

In an embodiment, the condition associated with aberrant ALK2 activityis anemia associated with inflammation, cancer or chronic disease.

In an embodiment, the condition associated with aberrant ALK2 activityis trauma- or surgery-induced heterotopic ossification.

In an embodiment, a compound of the disclosure is co-administered(either as part of a combination dosage form or as a separate dosageform administered prior to, sequentially with, of after administration)with a second therapeutic agent useful in treating the disease to betreated e.g., FOP. In one aspect of this embodiment, a compound of thedisclosure is co-administered with a steroid (e.g., prednisone) or otheranti-allergenic agents such as omalizumab.

In an embodiment, a compound of the disclosure is co-administered with aRAR-γ agonist or an antibody against activing for treating the diseaseto be treated e.g., FOP. In an embodiment, the RAR-γ agonist to beco-administered is palovarotene. In an embodiment, the antibody againstactivin to be co-administered is REGN2477.

In an embodiment, a compound of the disclosure is co-administered withtherapies that target mast cells useful in treating FOP. In anembodiment, a compound of the disclosure is co-administered with a mastcell inhibitor including, but not limited to a KIT inhibitor. In anembodiment, the mast cell inhibitor to be co-administered is selectedfrom cromolyn sodium (or sodium cromoglicate); brentuximab (ADCETRIS®);ibrutinib (IMBRUVICA®); omalizumab (XOLAIR®); anti-leukotriene agents(e.g., montelukast (SINGULAIR®) or zileuton (ZYFLO® or ZYFLO CR®)); andKIT inhibitors (e.g., imatinib (GLEEVEC®), midostaurin (PKC412A),masitinib (MASIVET® or KINAVET®), BLU-285, DCC-2618, PLX9486).

Synthesis

The Schemes below are meant to provide general guidance in connectionwith preparing the compounds of the disclosure. One skilled in the artwould understand that the preparations shown in the Schemes can bemodified or optimized using general knowledge of organic chemistry toprepare various compounds of the disclosure.

Synthetic Protocol 1

The pyrrolopyridazine 1 having a leaving group (LG₂) can be coupled witha functionalized piperazine 2 via a substitution reaction to provide anintermediate 3 with a new carbon-nitrogen bond formed. Thefunctionalized piperazine 2 can be formed by reaction with such groupsas carboxylic acids/acid chlorides, chloroformates and isocyanates (oractivated carbamates, etc.) to form amides, carbamates and ureas,respectively, via well-established reaction protocols; followed bydeprotection (if necessary). The resulting pyrrolopyridazine 3 can becoupled to intermediate 4 via a palladium-mediated coupling reaction,e.g., Suzuki, Stille, or Negishi coupling, to provide an intermediate(5) with a new carbon-carbon bond formed. (LG² can be, e.g., Cl, Br, orI. Z can be boronate, boronate ester, or trialkyltin. R^(2′) can be, forexample, Br, OH, N-linked alkyl or cycloalkylamine, or C-linked alkyl orcycloalkylamine. The resulting intermediate 5 can be furtherfunctionalized (following protecting group removal, if necessary) bycapping reactions including alkylation, reductive amination withcarbonyl containing compounds, acylation, ether formation via Mitsunobucoupling, amination using the Buchwald reaction, oralkyl/cycloalkylamine formation achieved through vinylboronic acidaddition followed by hydrogenation. Synthesis of exemplary compoundsprepared using Synthetic Protocol 1 are disclosed in certain of theExamples below.

Synthetic Protocol 2

The pyrrolopyridazine 1 can be coupled with a functionalized piperazine2 via a substitution reaction to provide an intermediate with a newcarbon-nitrogen bond formed. The resulting intermediate can be convertedto a boronate ester by palladium mediated coupling with bis-pinacolatodiboron to give intermediate 3′. In some instances, the R¹ group can bereplaced with a different R¹ group e.g., replacement nitrophenyloxy withoxetanyloxy. The resulting pyrrolopyridazine boronate can be coupled toan aryl halide (4′) via a palladium-mediated coupling reaction, e.g.,Suzuki coupling, to provide an intermediate with a new carbon-carbonbond formed. (LG² can be Cl, Br, I, OTf; R^(2′) can be, for example, Br,OH, N-linked alkyl or cycloalkylamine, or C-linked alkyl orcycloalkylamine.) This resulting di-substituted pyrrolopyridazine,intermediate 5, can be further functionalized (following protectinggroup removal, if necessary) by capping reactions including alkylation,reductive amination with carbonyl containing compounds, acylation, etherformation via Mitsunobu coupling between a phenol and alcohols,amination using the Buchwald reaction or alkyl/cycloalkylamine formationachieved through vinylboronic acid addition followed by hydrogenationvia well-established reaction protocols. Synthesis of exemplarycompounds prepared using Synthetic Protocol 2 are disclosed in certainof the Examples below.

Synthetic Protocol 3

The pyrrolopyridazine 7 can be coupled with substituted aryl boronicacids 4 (R^(2′) can be, for example, Br, OH, N-linked alkyl orcycloalkylamine, or C-linked alky or cycloalkylamine) to form a newcarbon-carbon bond. The resulting intermediate 8 can be furtherfunctionalized (following protecting group removal, if necessary) bycapping reactions including alkylation, reductive amination withcarbonyl containing compounds, acylation, ether formation via Mitsunobucoupling, or amination using the Buchwald reaction. Removal of the BOCgroup in intermediate 9 can be followed by capping reactions of theresulting free NH using activated carboxylic acids, chloroformates,carbamoyl chlorides/isocyanates to give amides, carbamates, or ureasrespectively via well-established reaction protocols. Synthesis ofexemplary compounds prepared using Synthetic Protocol 3 are disclosed incertain of the Examples below.

Synthetic Protocol 4

The pyrrolopyridazine boronate ester 10 can be coupled with aryl halides4′ to provide intermediate 8. (LG² can be, e.g., Cl, Br, or I. R^(2′)can be, for example, Br, OH, N-linked alkyl or cycloalkylamine, orC-linked alky or cycloalkylamine). Intermediate 8 can be furtherfunctionalized (following protecting group removal, if necessary) bycapping reactions including alkylation, reductive amination withcarbonyl containing compounds, acylation, ether formation via Mitsunobucoupling, or amination using the Buchwald reaction to provideintermediate 9. Removal of the BOC group in intermediate 9 can befollowed by capping reactions of the resulting free NH using activatedcarboxylic acids, chloroformates, carbamoyl chlorides/isocyanates togive amides, carbamates, or ureas respectively via well-establishedreaction protocols. Synthesis of exemplary compounds prepared usingSynthetic Protocol 4 are disclosed in certain of the Examples below.

Synthetic Protocol 5

The pyrrolopyridazine bromide 7 can be converted to the boronate ester10, via a Pd-mediate reaction. Removal of the BOC group in intermediate10 can be followed by capping reactions of the resulting free NH usingactivated carboxylic acids, chloroformates, carbamoylchlorides/isocyanates to give amides, carbamates, or ureas respectivelyvia well-established reaction protocols. The pyrrolopyridazine boronateester 3′ can be coupled with aryl halides 4′ to provide intermediate 5.(LG² can be, e.g., Cl, Br, or I. R^(2′) can be, for example, Br, OH,N-linked alkyl or cycloalkylamine, or C-linked alky or cycloalkylamine).Intermediate 5 can be further functionalized (following protecting groupremoval, if necessary) by capping reactions including alkylation,reductive amination with carbonyl containing compounds, acylation, etherformation via Mitsunobu coupling, or amination using the Buchwaldreaction to provide 6. Synthesis of exemplary compounds prepared usingSynthetic Protocol 5 are disclosed in certain of the Examples below.

In yet another embodiment, the disclosure provides an intermediate forsynthesizing compounds of the disclosure. The intermediate is6-bromopyrrolo[1,2-b]pyridazin-4-ol:

In another embodiment, the disclosure provides a process forsynthesizing said intermediate. The method of synthesizing6-bromopyrrolo[1,2-b]pyridazin-4-ol comprises the step of combining acompound of Formula C-1:

with a compound of Formula D-1:

wherein:

-   -   R²¹ is selected from chloro, bromo, and iodo;    -   R²² is a leaving group; and    -   R²³ is an electron withdrawing group.

In some embodiments, R²¹ is bromo.

In some embodiments, R²² is selected from —N(R²⁴)(R²⁵) and —OR²⁴,wherein each of R²⁴ and R²⁵ is an independently selected C₁-C₄ alkyl. Inmore specific aspects of these embodiments, R²² is —N(CH₃)₂.

In some embodiments, R²³ is selected from methylcarbonyl,t-butylcarbonyl, 4-nitrophenylcarbonyl, 4-cyanophenylcarbonyl,4-trifluoromethylphenylcarbonyl, 4-fluorophenylcarbonyl,4-trifluoromethylcarbonylphenylcarbonyl, 4-ethoxycarbonylphenylcarbonyl,4-trifluoromethylsulfonylphenylcarbonyl, 2,4,6-trimethylphenylcarbonyl,2,4,6-trimethyl-3,5-dinitrophenylcarbonyl,2-trifluoromethyl-4-nitrophenyl, 2,4-dintirophenyl anddiphenylphosphinyl. In more specific aspects of these embodiments, R²³is 4-nitrophenylcarbonyl.

In the method of synthesizing 6-bromopyrrolo[1,2-b]pyridazin-4-ol fromC-1 and D-1, the starting materials are dissolved in a polar solvent.The choice of polar solvent can be made from any known in the art. Morespecifically, the polar solvent is selected from N-methyl-2-pyrrolidine(“NMP”), N,N-dimethylacetamide (“DMAC”), dimethylformamide (“DMF”),tetrahydrofuran (“THF”), methyl-tetrahydrofuran (“MeTHF”), dimethylsulfoxide (“DMSO”), and cyclopentylmethyl ether (“CPME”). Even morespecifically, the polar solvent is NMP or DMAC.

In the first step of the synthesis method C-1 dissolved in the polarsolvent. This is done at the lowest temperature possible which allowsdissolution. Dissolved C-1 is then treated with a base, typically1.15-1.5 equivalents thereof, optionally maintained under a N₂atmosphere. The choice of base can be made from any known in the art.More specifically, the base is selected from KOC(CH₃)₃, NaOC(CH₃)₃,LiOC(CH₃)₃, LiC(CH₃)₃, Li(CH₂)₃CH₃, LiN(C₃H₇)₂, NaOCH₃, NaOCH₂CH₃,KOCH₃, LiOCH₃, LiOCH₂CH₃, and KOCH₂CH₃. Even more specifically, the baseis KOC(CH₃)₃.

Treatment of C-1 with a base is performed at a temperature of betweenabout 15 to 30° C. for 0.5-2 hours with stirring. The base-treated C-1solution is then optionally cooled to −8 to −5° C. before adding reagentD-1.

D-1 is also dissolved in a polar solvent at a temperature of between −5to 30° C. optionally under a N₂ atmosphere and then slowly added tobase-treated C-1. The resulting mixture is stirred for 1-2 hrs until atleast 90% of C-1 has disappeared as determined by LCMS or IPC.

At that point a protonating agent is added at acid pH and at atemperature of between about −5 to 10° C. The choice of protonatingagent can be made from any known in the art. More specifically, theprotonating agent is selected from NH₄Cl, NaHCO₃, KHCO₃, LiHCO₃, aceticacid, HCl, HBr, and H₂SO₄. Even more specifically, the protonating agentis NH₄Cl. In some specific aspects, the pH of the reaction with theprotonating agent is adjusted to between about 1 and 5, morespecifically between about 2 and 4 with an acidifying agent. In certainspecific embodiments, the acidifying agent is HCl. The protonationreaction is allowed to proceed for between 0.5-2 hrs at 0-10° C.

The resulting mixture is then optionally filtered before extracting theinsoluble material with an extraction agent. If filtered, the filtercake is extracted multiple times with the extraction agent and filteredafter each extraction. The original filtrate is then combined with allof the extraction filtrates and the resulting solution is allowed toseparate into an organic and an aqueous phase. The aqueous phase is thenextracted several more times with the extraction agent and all organicphases are combined. If the mixture resulting from the protonationreaction is not filtered, it is extracted multiple times with theextraction agent, with all organic phases resulting from the extractionsbeing pooled.

The choice of extraction agent may be made from any agent known in theart that is capable of extracting material from an aqueous phase into anorganic phase. More specifically, the extraction agent is selected frommethyl tert-butyl ether (“MTBE”), MeTHF, dichloromethane (“DCM”), CPME,diethyl ether, ethyl acetate, toluene, and isopropyl acetate. Even morespecifically, the extraction agent is MTBE.

The pooled organic layers resulting from the extractions are optionallywashed with saturated NaCl, dried over anhydrous Na₂SO₄, filtered if anyinsoluble material remains, and the soluble material then concentratedto dryness. This process typically results in at least 90% pure6-bromopyrrolo[1,2-b]pyridazin-4-ol as determined by LCMS, HPLC orquantitative ¹H-NMR.

EXAMPLES

The following examples are intended to be illustrative, and are notmeant in any way to be limiting.

Compounds of the disclosure, including salts and N-oxides thereof, canbe prepared using known organic synthesis techniques and can besynthesized according to any of numerous possible synthetic routes, suchas those in the Schemes below. The reactions for preparing compounds ofthe disclosure can be carried out in suitable solvents which can bereadily selected by one of skill in the art of organic synthesis.Suitable solvents can be substantially non-reactive with the startingmaterials (reactants), the intermediates, or products at thetemperatures at which the reactions are carried out, e.g., temperatureswhich can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected by the skilled artisan.

Preparation of compounds of the disclosure can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Wuts and Greene,Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: NewJersey, (2006), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., ¹Hor ¹³C), infrared (IR) spectroscopy, spectrophotometry (e.g.,UV-visible), mass spectrometry (MS), or by chromatographic methods suchas high performance liquid chromatography (HPLC) or thin layerchromatography (TLC). Analytical instruments and methods for compoundcharacterization include the following:

LC-MS:

Unless otherwise indicated, all liquid chromatography-mass spectrometry(LC-MS) data (sample analyzed for purity and identity) were obtainedwith an Agilent model-1260 LC system using an Agilent model 6120 ormodel 1956 mass spectrometer utilizing ES-API ionization fitted with anAgilent Poroshel 120 (EC-C18, 2.7 μm particle size, 3.0×50 mmdimensions) reverse-phase column at 22.4 degrees Celsius. The mobilephase consisted of a mixture of solvent 0.1% formic acid in water and0.1% formic acid in acetonitrile. A constant gradient from 95%aqueous/5% organic to 5% aqueous/95% organic mobile phase over thecourse of 4 minutes was utilized. The flow rate was constant at 1mL/min.

Alternatively, LC-MS data was obtained using the following columns andmobile phases. Basic Mobile Phase: A: water (10 mM NH₄HCO₃) B: ACN;Gradient: 5% B increase to 95% B within 1.2 min, 95% B for 1.3 min, backto 5% B within 0.01 min; Flow Rate: 2 mL/min; Column: XBridge, 3.5 um,50*4.6 mm; Oven Temperature: 50° C. Acidic Mobile Phase: A: water (0.01%TFA) B: CAN (0.01% TFA); Gradient: 5% B increase to 95% B within 1.2min, 95% B for 1.3 min, back to 5% B within 0.01 min; Flow Rate: 2mL/min; Column: Sunfire, 3.5 um, 50*4.6 mm; Oven Temperature: 50° C.

Alternatively, HPLC data was obtained using the following columns andmobile phases. Basic Mobile Phase: A: water (10 mM NH₄HCO₃) B: ACN;Gradient: 5% B increase to 95% B within 1.2 min, 95% B for 1.3 min, backto 5% B within 0.01 min; Flow Rate: 2 mL/min; Column: XBridge, 3.5 um,50*4.6 mm; Oven Temperature: 50° C. Acidic Mobile Phase: A: water (0.01%TFA) B: ACN (0.01% TFA); Gradient: 0 min 5% B, 3 min 5% B, 10 min 95% B,15 min 95% B; Flow Rate: 1.2 mL/min; Column: Eclipse XDB-C18, 4.6*150mm, 5 um; Oven Temperature: 40° C.

Prep LC-MS:

Preparative HPLC was performed on a Shimadzu Discovery VP® Preparativesystem fitted with a Luna 5u C18(2) 100A, AXIA packed, 250×21.2 mmreverse-phase column at 22.4 degrees Celsius. The mobile phase consistedof a mixture of solvent 0.1% formic acid in water and 0.1% formic acidin acetonitrile. A constant gradient from 95% aqueous/5% organic to 5%aqueous/95% organic mobile phase over the course of 25 minutes wasutilized. The flow rate was constant at 20 mL/min. Reactions carried outin a microwave were done so in a Biotage Initiator microwave unit.

Chiral HPLC:

Preparative HPLC to resolve chiral mixtures was performed on one of thefollowing systems. For SFC using either a SFC-80 or SFC-200 (Thar,Waters) instrument, we used an AD-H 20×250 mm, 5 μm Diacel column run at35° C. using a mobile phase gradient of CO₂/Methanol (0.1%NH₄OH)=40:60-90:10 at a flow rate of 80-180 g/min and detection at214-360 nm. For HPLC using a Gilson-281 instrument, we used an AD-H20×250 mm, 10 μm Diacel column run at 40° C. using a mobile phasegradient of Hexane (0.1% DEA): EtOH(0.1% DEA)=0:100-100:0.

Silica Gel Chromatography:

Silica gel chromatography was performed on either a Teledyne IscoCOMBIFLASH® Rf unit or a BIOTAGE® Isolera Four unit.

Proton NMR:

Unless otherwise indicated, all ¹H NMR spectra were obtained with aVarian 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time=3.5seconds with a 1 second delay; 16 to 64 scans), a Bruker, AVANCE III 500MHz UltraShield-Plus digital NMR spectrometer, or a Bruker, AVANCE III400 MHz UltraShield-Plus digital NMR spectrometer. Where characterized,all protons were reported in DMSO-d6 solvent as parts-per million (ppm)with respect to residual DMSO (2.50 ppm).

EXAMPLES

The following examples are intended to be illustrative, and are notmeant in any way to be limiting.

The below Schemes are meant to provide general guidance in connectionwith preparing the compounds of the disclosure. One skilled in the artwould understand that the preparations shown in the Schemes can bemodified or optimized using general knowledge of organic chemistry toprepare various compounds of the disclosure.

Example 1. Synthesis of 6-bromopyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonate Step 1: Synthesis of1-(4-bromo-1H-pyrrol-2-yl)ethanone (Intermediate B)

Amberlyst 15 (0.09 g/g-bulk-LR) was added to a solution of commerciallyavailable 1-(1H-pyrrol-2-yl)ethanone (70 g; 1.00 equiv; 641.45 mmoles)in tetrahydrofuran (10 mL/g-bulk-LR; 9.71 moles; 700.00 mL; 700.00 g) atroom temperature (RT) (around 25° C.). Next,1-bromopyrrolidine-2,5-dione (1 equiv (molar); 641.45 mmoles; 114.17 g)was added in portions at −30 to −20° C. and stirred for approximately 1h until LCMS indicated that the reaction was complete. The reactionmixture was then filtered and the filtrate quenched with saturatedNa₂SO₃ aqueous (350 mL) and extracted with DCM (700 mL×2). The organiclayer was concentrated and then diluted with MTBE (700 mL). The organiclayers were combined and then washed with sat.NaHCO₃ (350 mL×2) andconcentrated on a rotavapor under reduced pressure to give1-(4-bromo-1H-pyrrol-2-yl)ethanone (Intermediate B; 91 g; 0.75 equiv;483.98 mmoles; 91.00 g; 75.45% yield) as a white solid. LCMS: 100%purity.

Step 2: Synthesis of(E)-1-(4-bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one(Intermediate C)

1-(4-bromo-1H-pyrrol-2-yl)ethanone (50 g; 1.00 equiv; 265.92 mmoles;50.00 g) was added to 1,1-dimethoxy-N,N-dimethylmethanamine (5mL/g-pure-LR; 2.10 moles; 250.00 mL; 250.00 g;) at room temperature(around 25° C.) and then the reaction mixture was heated at 70˜80° C.for 12 h when LCMS indicated that the reaction was complete resulting ina suspension. The reaction mixture was filtered and the cake washed withPE (300 mL). The wet cake was dried in air for 16 h to give(E)-1-(4-bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one (35 g;0.54 equiv; 143.97 mmoles; 35.00 g; 54.14% yield) as a yellow solid.LCMS: >95%.

Step 3: Synthesis of 6-bromopyrrolo[1,2-b]pyridazin-4-ol (IntermediateE)

(E)-1-(4-bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one (C; 20g; 1.00 equiv; 82.27 mmoles; 20.00 g;) was taken up in1-methylpyrrolidin-2-one (30 mL/g-bulk-LR; 6.05 moles; 600.00 mL; 600.00g) to form a solution. Potassium 2-methylpropan-2-olate (1.5 equiv(molar); 123.40 mmoles; 13.85 g) was then added in portions. Thesolution temperature was kept at 10 to 25° C. and the solution was thenstirred at 15 to 25° C. for 0.5 h. Commercially availableO-(4-nitrobenzoyl)hydroxylamine (D; 1.5 equiv (molar); 123.40 mmoles;22.48 g) was then added into the reaction mixture maintaining thetemperature at 20 to 30° C. and then stirred at 30° C. for 2 h untilLCMS indicated that the starting material was gone. Saturated aqueousammonium chloride (200 mL) was added dropwise into the reaction mixturecooled in an ice bath (0° C.), diluted with water (200 mL), and the pHwas adjusted to between 3 and 4 with hydrochloric acid (1 M). Theresulting solution was extracted with MTBE (3×150 mL), the combinedorganic layers were dried over anhydrous sodium sulfate, and thenfiltered and concentrated to dryness. The residue was purified by silicagel chromatography (petroleum ether: ethyl acetate=10:1-5:1) to give6-bromopyrrolo [1,2-b]pyridazin-4-ol (E; 16 g, 90% yield; Purity:91.6%)and isolated as a yellow solid, which is used for next step withoutfurther purifications. LCMS: 91.6%.

Step 3 Alternate: Synthesis of 6-bromopyrrolo [1,2-b]pyridazin-4-ol(Intermediate E)

A synthesis of Intermediate E using the same reagents, but differentconditions, is described in this Step 3 Alternate.

Two hundred kilograms of DMAc was added into a reactor to which was thenquickly added. potassium tert-butoxide (1.15 equiv) under protection ofN₂. The mixture was stirred until the reagents were dissolved.((E)-1-(4-bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one)(C;20.5 kg, 84.32 mol, 1 equiv) was added and was kept stirring at 20-30°C. for 1-2 hours. The reaction mixture was then cooled to −8 to −5° C.O-(4-nitrobenzoyl)hydroxylamine (D; 16.1 kg, 88.54 mol, 1.05 equiv) wasthen dissolved into DMAc (100 kg) in a separate container and thesolution maintained at −5-0° C., then slowly the resulting solution of Dwas added to the reaction mixture. During addition, the temperature ofsolution D was maintained at −5-0° C. and kept under N₂ protection. Theaddition of D was completed after about 4 hrs. The resulting mixture wascontinually stirred at −5-0° C. for an additional 1-2 hr, until lessthan 8% of starting material C was present as determined by IPC.Saturated NH₄Cl (150 kg) was added at −5-10° C. and the pH was adjustedto 2-2.5 with hydrochloric acid also maintained at −5-10° C. The mixturewas continually stirred for an additional 1-2 hrs at 0-10° C. Theresulting mixture was then filtered, and the filter cake washed twicewith MTBE (100 kg×2). The filtrates were combined, and the aqueous layerseparated from the organic layer. The aqueous layer was then extractedwith MTBE 4-5 times and all of the organic phases were combined. Theorganic phases were then washed with sat. NaCl (40 kg×3). The organicphases were dried over anhydrous Na₂SO₄, filtered and the filtrate wasconcentrated at 35-45° C. under vacuum until the solution volume was ˜50L (this concentration process should be completed within 3 hrs). Theresulting concentrated solution was separated into several smallerbatches and each batch transferred to a rotary evaporator for furtherand faster concentration to give wet solid (this process should becompleted within 2 hrs). The resulting wet solids were combined and thenDCM (40 kg) was added to slurry wash the solid at 10-15° C. for 0.5 h.The slurry was then filtered and dried to give 7.45 kg of E (HPLC:98.51%, RRT=˜1.4 impurity is 1.28%, QHNMR: 96.72%, assay by externalstandard method is 94.5%, yield is 41.4%).

Step 4: Synthesis of 6-bromopyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonate (Intermediate F)

6-bromopyrrolo[1,2-b]pyridazin-4-ol (E; 10 g; 1.00 equiv; 46.94 mmoles;10.00 g), dichloromethane (15 mL/g-bulk-LR; 2.34 moles; 150.00 mL;198.75 g) and triethylamine (1.18 equiv (molar); 55.39 mmoles; 7.68 mL;5.61 g) were combined in a 250 mL reactor. Trifluoromethanesulfonicanhydride (1.15 equiv (molar); 1.15 equiv; 53.98 mmoles; 9.08 mL; 15.23g) was added dropwise and the temperature was kept between 0-20° C. Thereaction mixture was warmed to 25° C. and stirred for an additional 2 huntil LC-MS showed the reaction was completed. The mixture was thendiluted with DCM (160 mL) and washed with sat.NaHCO₃ solution (2×80 mL).The organic phases were combined and dried over Na₂SO₄, filtered andconcentrated under reduced pressure. MTBE (80 mL) and PE (80 mL) wereadded to dilute the crude product with stirring. Any solid thatprecipitated out at the bottom was removed by filtration. The filtratewas washed with sat. NaHCO₃ (40 mL×2) and water (40 mL) and sat. NaCl(40 mL) and then concentrated to give a crude product. Furtherpurification was achieved with silica chromatography (PE/MTBE=100/0 to50/1) to give 6-bromopyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonate (F; 9 g; 0.56 equiv; 26.08 mmoles; 9.00 g;55.56% yield; [Actual]) as a dark green liquid. LC-MS: 345 (M+H)⁺, 98%purity (214 nm).

Alternate Synthesis of Intermediate E

An alternate synthesis of Intermediate E was carried out as follows

Step 1: 6-bromo-4-hydroxy-pyrrolo[1,2-b]pyridazine-3-carbonitrile

To a solution of methyl 1-amino-4-bromo-pyrrole-2-carboxylate (4.0 g, 18mmol, 1.0 eq) and 3,3-dimethoxypropanenitrile (12.6 g, 109 mmol, 6.0 eq)was added TsOH (629 mg, 4 mmol, 0.2 eq). The reaction mixture wasstirred at 80° C. for 6 h. Then, DBU (16.7 g, 109 mmol, 6.0 eq) wasadded into the reaction mixture and stirred for another 10 h at 80° C.TLC showed the reaction was complete. The mixture was diluted with water(5 mL) and extracted with EA (10 mL×2). The combined organic phases werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM:MeOH=10:1)to give the title product (3.7 g, 15 mmol, 85% yield) as a yellow solid.

Step 2: 6-bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxamide

To the solution of6-bromo-4-hydroxy-pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.0 g, 8.4mmol, 1.0 eq) in EtOH (20 mL) was added a solution of NaOH (16.0 g, 400mmol) in H₂O (50 mL). The reaction mixture was stirred for 48 h at 100°C. until TLC (petroleum ether (PE): ethyl acetate (EA)=0:1) indicatedthat most of the starting material was consumed. The reaction mixturewas concentrated to remove the EtOH. The pH of the resulting aqueoussolution was adjusted to 5-6 and then extracted with ethyl acetate. Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=5:1-1:1) to afford thetitle product (1.1 g, 4 mmol, 51% yield) as a yellow solid.

Step 3: 6-bromopyrrolo[1,2-b]pyridazin-4-ol (Intermediate E)

To a solution of 6-bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxamide(1.0 g, 4 mmol) in concentrated HCl (aq., 30 mL) was added dioxane (2mL) and EtOH (2 mL). The reaction mixture was stirred for 48 h at 100°C. TLC (petroleum ether:ethyl acetate=0:1) indicated that most of thestarting material was consumed and the reaction mixture was concentratedto remove organic solvents. The pH of the resulting aqueous solution wasadjusted to 4-6 and then extracted (twice) with ethyl acetate. Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=10:1-5:1) to afford crudeIntermediate E (150 mg, contains two byproducts (halogen-exchange andde-halogen)) as a yellow solid.

Example 2. Synthesis ofcyclopropyl(4-(6-(4-(piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 127) Step 1: Synthesis of(4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone

A mixture of 6-bromopyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonate (30 g, 86.9 mmol),cyclopropyl(piperazin-1-yl)methanone (16.0 g, 104 mmol), andtriethylamine (13.1 g, 130 mmol) in NMP (300 mL) was stirred at 100° C.for 30 min. The reaction mixture was cooled and diluted with EA. Theorganic layer was washed with water and brine, concentrated and purifiedby silica gel column to give the title product (26.0 g, yield 86%) as ayellow solid. MS (ES+) C₁₅H₁₇BrN₄O requires: 348, found: 349 [M+H]⁺.

Step 2: Synthesis ofcyclopropyl(4-(6-(4-(piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 127)

A mixture of(4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(3.0 g, 8.59 mmol),1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazinehydrochloride (3.10 g, 12.8 mmol), K₂CO₃ (4.73 g, 34.3 mmol) andPd(dppf)Cl₂.CH₂Cl₂ (700 mg, 859 μmol) in 1,4-dioxane/water (30 mL/5 mL)was degassed with N₂, and then stirred at 100° C. for 16 h under N₂. Themixture was cooled to RT and concentrated. The residue was purified bysilica gel column to give the title product (1.95 g, yield 52.8%) as awhite solid. MS (ES+) C₂₅H₃₀N₆O requires: 430, found: 431 [M+H]⁺.

Example 3. Synthesis ofcyclopropyl(4-(6-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 274)

A mixture ofcyclopropyl(4-(6-(4-(piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(100 mg, 232 μmol), 2-bromoethanol (57.9 mg, 464 μmol) and potassiumcarbonate (32 mg, 0.232 mmol) was stirred at 70° C. overnight (˜12 h).The reaction mixture was cooled and concentrated. The residue waspurified by Prep-HPLC to afford the title compound as a white solid(10.5 mg, yield 9.5%). MS (ES+) C₂₇H₃₄N₆O₂, requires: 474, found: 475[M+H]⁺.

Example 4. Synthesis ofcyclopropyl(4-(6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 314) Step 1: Synthesis of tert-butyl4-(4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)phenyl)piperazine-1-carboxylate

A mixture of(4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(65 mg, 0.19 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(86 mg, 0.22 mmol), K₂CO₃ (51 mg, 0.37 mmol) and Pd(dppf)Cl₂ (14 mg,0.019 mmol) in dioxane/water (10/1) was irradiated in the microwave at100° C. for 1 h. Concentrated and purified by flash column (PE/EA=2/1 to1/10) to give the title product (66 mg, yield 65.4%). MS (ES+)C₃₀H₃₈N₆O₃, requires: 530, found 531[M+H]⁺.

Step 2: Synthesis ofcyclopropyl(4-(6-(4-(piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone

To a solution of tert-butyl4-(4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)phenyl)piperazine-1-carboxylate(66 mg, 0.12 mmol) in DCM was added TFA (TFA/DCM, 10:1). The reactionmixture was stirred at RT for 1 h. Saturated NaHCO₃ solution was addedto the mixture to bring the pH to 8-9, and then the mixture wasextracted with DCM. The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated to give the title product (55 mg,crude). MS (ES+) C₂₅H₃₀N₆O, requires: 430, found 431 [M+H]⁺.

Step 3: Synthesis ofcyclopropyl(4-(6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone

To a solution ofcyclopropyl(4-(6-(4-(piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(55 mg, crude) in 1,2-dichloroethane was added oxetan-3-one (92 mg, 1.27mmol), followed by addition of NaBH(OAc)₃ (269 mg, 1.27 mmol). Thereaction mixture was stirred at RT overnight. Concentration andpurification by Prep-HPLC gave the title product (3.7 mg, yield 6.3%).MS (ES+) C₂₈H₃₄N₆O₂ requires: 486, found 487 [M+H]⁺.

Example 5. Synthesis ofcyclopropyl(4-(6-(4-(2-(piperazin-1-yl)ethoxy)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 273) and(4-(6-(4-(2-(4-ethylpiperazin-1-yl)ethoxy)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 390) Step 1: Synthesis of tert-butyl4-(2-(4-bromophenoxy)ethyl)piperazine-1-carboxylate

A mixture of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (400mg, 1.73 mmol), MsCl (596 mg, 5.19 mmol) and triethylamine (524 mg, 5.19mmol) in DCM (25 mL) was stirred at RT for 2 h. The solution was dilutedwith DCM, and washed with sat. NaHCO₃ and brine. The organic layer wasconcentrated. The residue was dissolved in DMF (15 mL), followed byaddition of 4-bromophenol (451 mg, 2.61 mmol) and Cs₂CO₃ (1.70 g, 5.22mmol) at RT. The resultant mixture was stirred at 100° C. for 18 h.After that, the solution was diluted with EA and washed with brine. Theorganic layer was concentrated and purified by silica gel chromatographyto get the title compound (320 mg, yield 48%) as a colorless oil. MS(ES+) C₁₇H₂₅BrN₂O₃ requires: 384, 386 found: 385, 387 [M+H]⁺.

Step 2: Synthesis of tert-butyl4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine-1-carboxylate

A mixture of tert-butyl4-(2-(4-bromophenoxy)ethyl)piperazine-1-carboxylate (320 mg, 830 μmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (271 mg,1.07 mmol), Pd(dppf)Cl₂ (60.6 mg, 83.0 μmol) and KOAc (325 mg, 3.32mmol) in dioxane/water (10 mL) was purged with N₂, and stirred at 100°C. for 18 h under N₂. After that, the solution was cooled andconcentrated. The residue was purified by silica gel chromatography(EA/PE=1/3) to get the title compound (300 mg, yield 84%) as a brownoil. MS (ES+) C₂₃H₂₇BN₂O₅ requires: 432, found: 433 [M+H]⁺.

Step 3: Synthesis of tert-butyl4-(2-(4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate

A mixture of(4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(200 mg, 572 μmol), tert-butyl4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine-1-carboxylate(271 mg, 629 μmol), Pd(dppf)Cl₂ (41.8 mg, 57.2 μmol), and K₂CO₃ (314 mg,2.28 mmol) in dioxane (5 mL) and water (1 mL) was purged with N₂, andthen stirred at 100° C. for 18 h under N₂. After that, the solution wascooled and concentrated. The residue was purified by silica gelchromatography to get the title compound (160 mg, yield 49%) as a yellowoil. MS (ES+) C₃₂H₄₂N₆O₄ requires: 574, found: 575 [M+H]⁺.

Step 4: Synthesis ofcyclopropyl(4-(6-(4-(2-(piperazin-1-yl)ethoxy)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 273)

A mixture of tert-butyl4-(2-(4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate(80 mg, 139 μmol) in HCl/dioxane (4 N, 1 mL) was stirred at RT for 2 h.After that, the solution was concentrated to afford the title compound(80 mg, crude) as a yellow solid. MS (ES+) C₂₇H₃₄N₆O₂ requires: 474found: 475 [M+H]⁺.

Step 5: Synthesis ofcyclopropyl(4-(6-(4-(2-(4-ethylpiperazin-1-yl)ethoxy)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 390)

A mixture of tert-butyl4-(2-(4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)phenoxy)ethyl)piperazine-1-carboxylate(40 mg, 84.2 μmol), CH₃CHO (11.0 mg, 252 μmol), NaBH₃CN (7.93 mg, 126μmol) and AcOH (5.05 mg, 84.2 μmol) in DCM (5 mL) and MeOH (2 mL) wasstirred at RT for 2 h. After that, the solution was concentrated andpurified by Prep-HPLC to give the title compound (12 mg, 28%) as ayellow solid. MS (ES+) C₂₉H₃₈N₆O₂ requires: 502 found: 503 [M+H]⁺.

Example 6. Synthesis ofcyclopropyl(4-(6-(1-(5,5-difluoropiperidin-3-yl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 194) Step 1: Synthesis of tert-butyl 5-oxo-5,6-dihydropyridine-1 (2H)-carboxylate

To a solution of 1-(tert-butoxycarboxyl)-1,2,3,6-tetrahydropyridin-3-ol(300 mg, 1.50 mmol) in DCM (25 mL) was added Dess-Martin Oxidant (1.27g, 3.00 mmol). The reaction solution was stirred at RT for 12 hours andthen filtered. The filtrate was washed with saturated aqueous Na₂CO₃ (50mL) and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=2/1) to give the title compound asa colorless oil (280 mg, yield 94%). MS (ES+) C₁₀H₁₅NO₃ requires: 197,found: 142 [M+H-56]⁺.

Step 2: Synthesis of(4-(6-(1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone

A mixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(335 mg, 1.14 mmol),(4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(400 mg, 1.14 mmol), Na₂CO₃ (362 mg, 3.42 mmol) and Pd(t-Bu₃P)₂ (116 mg,0.228 mmol) in dioxane/water (v/v=3:1, 10 mL) was degassed with N₂ threetimes, and then stirred at 85° C. for 12 hours. The reaction mixture wascooled and evaporated in vacuo. The residue was purified by flash column(PE:EA=3:1 to 1:3) to give the title compound as a yellow solid (340 mg,yield 88%). MS (ES+) C₁₈H₂₀N₆O requires: 336, found: 337 [M+H]⁺.

Step 3: Synthesis of tert-butyl3-(4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)-5-oxopiperidine-1-carboxylate

A mixture of tert-butyl 5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (100mg, 0.51 mmol) and(4-(6-(1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(180 mg, 0.54 mmol) in MeCN (5 mL) in a flask was evaporated in vacuo at50° C. The residue was diluted with 5 mL of MeCN, and then evaporated todryness. The dilution/evaporation was repeated three times. Purificationby flash column (PE/EA to EA) gave the title compound as an off-whitesolid (140 mg, yield 49%). MS (ES+) C₂₈H₃₅N₇O₄ requires: 533, found: 534[M+H]⁺.

Step 4: Synthesis of tert-butyl5-(4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)-3,3-difluoropiperidine-1-carboxylate

To a solution of tert-butyl3-(4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)-5-oxopiperidine-1-carboxylate(60 mg, 0.1124 mmol) in DCM (4 mL) was added DAST (180 mg, 1.12 mmol) at0° C. The reaction mixture was then stirred at 0° C. for 10 minutes.Quenched by water and extracted with DCM. The organic layers wereevaporated and purified by flash column (PE/EA=1:4 to 4:1) to give thetitle compound as a yellow solid (12 mg, yield 19%). MS (ES+)C₂₈H₃₅F₂N₇O₃ requires: 555, found: 556 [M+H]⁺.

Step 5: Synthesis ofcyclopropyl(4-(6-(1-(5,5-difluoropiperidin-3-yl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone

To a solution of tert-butyl5-(4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)-3,3-difluoropiperidine-1-carboxylate(12 mg, 0.02159 mmol) in DCM (2.0 mL) was added TFA (1.0 mL). Thereaction solution was stirred at 25° C. for 1 hour. The reactionsolution was concentrated in vacuo. The residue was dissolved in DCM andneutralized by sat. aqueous NaHCO₃. The organic layer was washed withbrine, dried and concentrated to give the title compound (8.5 mg, yield86%) as a yellow solid. MS (ES+) C₂₃H₂₇F₂N₇O requires: 455, found 456[M+H]⁺.

Example 7. Synthesis of(S)-cyclopropyl(4-(6-(4-(morpholin-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 130) and(R)-cyclopropyl(4-(6-(4-(morpholin-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 131) Step 1: Synthesis ofcyclopropyl(4-(6-(4,4,5,5-tetramethyl-,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone

A mixture of(4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(11.6 g, 33.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (16.8 g,66.4 mmol), Pd(dppf)Cl₂ (3.63 g, 4.97 mmol) and KOAc (9.76 g, 99.6 mmol)in CH₃CN (300 mL) was purged with N₂ and then stirred at 65° C. for 24hrs under N₂.

The reaction mixture was concentrated and purified by flashchromatography (PE/EA=10:1 to 2:1) to afford the title compound (11.2 g,80% yield) as a yellow solid. MS (ES+) C₂₁H₂₉BN₄O₃ requires: 396, found:397 [M+H]+.

Step 2: Synthesis of(S)-cyclopropyl(4-(6-(4-(morpholin-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 130) and(R)-cyclopropyl(4-(6-(4-(morpholin-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 131)

A mixture ofcyclopropyl(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(300 mg, 757 μmol), 2-(4-bromophenyl)morpholine (183 mg, 757 μmol),Pd(dppf)Cl₂—CH₂Cl₂ (61.7 mg, 75.7 μmol) and K₂CO₃ (208 mg, 1.51 mmol) indioxane/water (3 mL/0.5 mL) was purged with N₂, and then stirred at 100°C. for 16 hrs under N₂. The mixture was concentrated and purified byflash column chromatography (DCM/MeOH=10:1) to give a yellow oil (300mg, crude).Chiral separation was performed to afford the title compoundsusing a CE-3 column. Mobile Phase: Hexane/EtOH/DEA=30/70/0.1; flow rate:50 mL/min; 0.4 ml injection; 25 minute run time; sample solution: 3.2 gin 30 mL MeOH; elution measured at 214 and 254 nm using a Gilson-281.Compound 130: (56.3 mg, 17% yield) as a yellow solid MS (ES+) C₂₅H₂₉N₅O₂requires: 431, found: 432 [M+H]⁺. Compound 131: (32.6 mg, 10% yield) asa yellow solid. MS (ES+) C₂₅H₂₉N₅O₂ requires: 431, found: 432 [M+H]+.

Example 8. Synthesis ofcyclopropyl(4-(6-(4-(4-ethylmorpholin-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 214)

A mixture ofcyclopropyl(4-(6-(4-(morpholin-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(100 mg, 231 μmol) and acetaldehyde (40.7 mg, 924 μmol) inDCM/MeOH/CH₃COOH (2 mL/2 mL/0.5 mL) was stirred at 25° C. for 30 min,followed by addition of NaBH₃CN (72.2 mg, 1.15 mmol). The mixture wasstirred at 25° C. for 2 hours. The mixture was purified by Prep-HPLC toafford the title compound (8.4 mg, yield 8%) as a yellow solid. MS (ES+)C₂₇H₃₃N₅O₂ requires: 459, found: 460 [M+H]⁺.

Example 9. Synthesis ofcyclopropyl(4-(6-(4-(2-(trifluoromethyl)piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 374) Step 1: Synthesis of4-benzyl-1-(4-bromophenyl)-2-(trifluoromethyl)piperazine

A mixture of 1-benzyl-3-(trifluoromethyl)piperazine (200 mg, 818 μmol),1-bromo-4-iodobenzene (461 mg, 1.63 mmol),bis(tri-t-butylphosphine)palladium (83.3 mg, 163 μmol) and cesiumcarbonate (798 mg, 2.45 mmol) in toluene (4 mL) was purged with N₂ andstirred at 80° C. overnight. TLC and LCMS showed completed reaction. Themixture was cooled to RT and concentrated. The residue was purified bysilica gel column (PE/EA=10/1) to give the title compound (40 mg, yield12%) as a yellow solid. MS (ES+) C₁₈H₁₈BrF₃N₂ requires: 398, found: 399[M+H]⁺.

Step 2: Synthesis of(4-(6-(4-(4-benzyl-2-(trifluoromethyl)piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone

A mixture of 4-benzyl-1-(4-bromophenyl)-2-(trifluoromethyl)piperazine(60 mg, 150 μmol),cyclopropyl(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(118 mg, 300 μmol), Pd(dppf)Cl₂ (21.9 mg, 30.0 μmol) and potassiumcarbonate (62.1 mg, 450 μmol) in dioxane/water (4 mL) was purged with N₂and stirred at 100° C. for 2 h. TLC and LCMS showed completed reaction.The mixture was cooled to RT and concentrated. The residue was purifiedby silica gel column (PE/EA=2/1) to give the title compound (80 mg,crude) as a yellow solid. MS (ES+) C₃₃H₃₅F₃N₆O requires: 588, found: 589[M+H]⁺.

Step 3: Synthesis ofcyclopropyl(4-(6-(4-(2-(trifluoromethyl)piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 374)

A mixture of(4-(6-(4-(4-benzyl-2-(trifluoromethyl)piperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(70 mg, 118 μmol) and Pd/C (14 mg, 20% wt) in i-PrOH (4 mL) was stirredat 45° C. overnight under hydrogen (balloon). The mixture was filteredand concentrated. The residue was purified by Prep-HPLC to give thetitle compound (1.6 mg, yield 3%) as a white solid. MS (ES+) C₂₆H₂₉F₃N₆Orequires: 498, found: 499 [M+H]⁺.

Example 10. Synthesis of N-ethyl4-(6-(4-(1-ethylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(Compound 230) Step 1: Synthesis of6-(4-(1-ethylpiperidin-4-yl)phenyl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazine

A mixture of 6-bromo-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazinehydrochloride (1.2 g, 3.77 mmol),1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine(1.78 g, 5.65 mmol), K₂CO₃ (1.57 g, 11.3 mmol) and Pd(t-Bu₃P)₂ indioxane/water (20 mL/5 mL) was degassed with nitrogen three times. Themixture was then heated to 70° C. and the temperature maintainedovernight. The reaction mixture was cooled to RT and concentrated togive a residue, which was purified by silica gel chromatography toafford the title compound (1.2 g, yield 82%) as a yellow oil. MS (ES+)C₂₄H₃₁N₅ requires: 389, found: 390 [M+H]⁺.

Step 2: Synthesis of ethyl4-(6-(4-(1-ethylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(Compound 230)

To a solution6-(4-(1-ethylpiperidin-4-yl)phenyl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazine(50 mg, 128 μmol) and DIPEA (82 mg, 640 μmol) in DCM (10 mL) was addedethyl chloroformate (41.5 mg, 384 μmol). The reaction mixture wasstirred at RT for 3 h. The mixture was concentrated under reducedpressure. The residue was purified by Prep-HPLC to afford the titlecompound (9 mg, yield 15%). MS (ES+) C₂₇H₃₅N₅O₂ requires: 461, found:462 [M+H]⁺.

Example 11. Synthesis ofN-ethyl-4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxamide(Compound 275) Step 1: Synthesis oftert-butyl-4-(6-bromo-pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

A mixture of 6-bromopyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonate (200 g, 579.7 mmol), tert-butylpiperazine-1-carboxylate (113.2 g, 609 mmol) and triethylamine (176 g,1740 mmol) in NMP (180 mL) was stirred at 100° C. for 1 hr. Monitored byLC-MS, the reaction was completed. The mixture was diluted with EtOAc,washed with water and brine, and dried over sodium sulfate. The organiclayer was concentrated and purified by flash chromatography (silica gel,10-40% EtOAc in PE) to afford the title compound (220.0 g, crude). MS(ES+) C₁₆H₂₁BrN₄O₂ require: 380, 382, found: 381, 383 [M+H]+.

Step 2: Synthesis oftert-butyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate (220 gcrude, 0.58 mol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (294 g,1.158 mol), Pd(dppf)Cl₂—CH₂Cl₂ (42.4 g, 0.058 mol) and KOAc (170.2 g,1.737 mol) in CH₃CN (500 mL) was purged with N₂ and stirred at 65° C.for 24 hrs under N₂. Monitored by LC-MS, the reaction was completed. Themixture was cooled to RT, concentrated and purified by flash columnchromatography (Petroleum ether/ethyl acetate=10:1 to 2:1) to afford thetitle compound (189.0 g, 76%) as a white solid. MS (ES+) C₂₂H₃₃BN₄O₄requires: 428, found: 429 [M+H]+.

Step 3: Synthesis of tert-butyl tert-butyl4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

To a solution of 4-(4-bromophenyl)-1-isopropylpiperidine (300 mg, 1.06mmol) andtert-butyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(550 mg, 1.59 mmol) in dioxane/water (30 mL/10 mL) was added Pd(t-Bu₃P)₂(108.3 mg, 0.212 mmol) and Na₂CO₃ (337.1 mg, 3.18 mmol) at RT undernitrogen. The resulting mixture was heated at 75° C. for 3 hours; LCMSshowed that the reaction was completed. Water (50 mL) was added andextracted with EtOAc (50 mL×2). The organic layer was washed with brine(50 mL), dried over Na₂SO₄, and concentrated to dryness to afford crudeproduct, which was purified with flash column (DCM/MeOH, 10:1) to givethe title compound (346 mg, yield 65%) as a white powder. MS (ES+)C₃₀H₄₁N₅O₂, requires: 503, found: 504 [M+H]⁺.

Step 4: Synthesis of6-(4-(1-isopropylpiperidin-4-yl)phenyl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazinehydrochloride

To a solution of tert-butyl4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(346 mg, 0.69 mmol) in dioxane (10 mL) was added 6 M HCl/dioxane (3 mL)at RT. The resulting mixture was stirred for 6 hours; LCMS showed thatthe reaction was completed. The mixture was then evaporated to drynessto afford the title product (282 mg, 93% yield) as a white solid. MS(ES+) C₂₅H₃₃N₅ requires: 403, found: 404 [M+H]⁺.

Step 5: Synthesis ofN-ethyl-4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxamide(Compound 275)

To a solution of6-(4-(1-isopropylpiperidin-4-yl)phenyl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazinehydrochloride (282 mg, 0.64 mmol) in DCM (10 mL) was added triethylamine(0.5 mL) and isocyanatoethane (0.1 mL) at 0° C. The resulting mixturewas stirred at RT for 30 min; LCMS indicated that the reaction wascompleted. Extracted with EtOAc (50 mL×2) after water (50 mL) was added.The organic layer was washed with brine (50 mL), dried over Na₂SO₄, andconcentrated to dryness to afford crude product which was purified byPrep-HPLC to give the title compound (89.9 mg, yield 30%) as a whitepowder. MS (ES+) C₂₇H₃₇N₇O, requires: 475, found: 476 [M+H]⁺.

Example 12. Synthesis ofcyclopropyl(4-(6-(4-(1-isopropylazetidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 150) Step 1: Synthesis of tert-butyl4-(6-(4-(1-isopropylazetidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(680 mg, 1.59 mmol) in dioxane/water (15 mL) was added3-(4-bromophenyl)-1-isopropylazetidine (480 mg, 1.9 mmol), Pd(t-Bu₃P)₂(81 mg, 0.16 mmol) and Na₂CO₃ (337 mg, 3.18 mmol) at room temperatureunder nitrogen. The resulting mixture was stirred at 70° C. for 3 hunder nitrogen. Water was added and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated to dryness to afford crude compound, which was purified byflash chromatography on silica gel eluting with DCM/MeOH (10:1) to givethe title compound (430 mg, 57% yield) as a light yellow powder. MS(ES+) C₂₈H₃₇N₅O₂ requires: 475, found 476 [M+H]⁺.

Step 2: Synthesis of6-(4-(1-isopropylazetidin-3-yl)phenyl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazine

To a solution of tert-butyl4-(6-(4-(1-isopropylazetidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(430 mg, 0.91 mmol) in dioxane (10 mL) was added HCl/dioxane (3 mL, 4.0M) at RT. The resulting mixture was stirred for 5 hours. LC-MS showedthat the reaction was completed. The mixture was evaporated to drynessto afford the title compound (360 mg, 99% yield) as a white powder. MS(ES+) C₂₃H₂₉N₅ requires: 375, found 376 [M+H]⁺.

Step 3: Synthesis ofcyclopropyl(4-(6-(4-(1-isopropylazetidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone

To a solution of6-(4-(1-isopropylazetidin-3-yl)phenyl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazine(120 mg, 0.32 mmol) in DMF (10 mL) was added cyclopropanecarboxylic acid(33 mg, 0.38 mmol) and triethylamine (80 mg, 0.8 mmol) at RT, followedby addition of HATU (144 mg, 0.38 mmol). The resulting mixture wasstirred at RT for 2 h, diluted with water and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄, andconcentrated to dryness to afford crude product, which was purified byflash chromatography on silica gel eluting with DCM/MeOH (5:1) to givethe title compound (101 mg, 72% yield) as a white powder. MS (ES+)C₂₇H₃₃N₅O requires: 443, found 444 [M+H]⁺.

Example 13. Synthesis of ethyl4-(6-(5-(4-isopropylpiperazin-1-yl)pyrazin-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(Compound 448) Step 1: Synthesis of tert-butyl4-(5-bromopyrazin-2-yl)piperazine-1-carboxylate

A mixture of 2,5-dibromopyrazine (2 g, 8.40 mmol), tert-butylpiperazine-1-carboxylate (1.86 g, 10.0 mmol) and DIPEA (1.62 g, 12.6mmol) in NMP (40 mL) was stirred at 110° C. for 2 h. Diluted with ethylacetate, washed with water and brine, dried over Na₂SO₄, andconcentrated to give the title product (2.8 g, yield 97%). MS (ES+)C₁₃H₁₉BrN₄O₂ requires: 342, found: 343 [M+H]⁺.

Step 2: Synthesis of 2-bromo-5-(piperazin-1-yl)pyrazine

To a solution of tert-butyl4-(5-bromopyrazin-2-yl)piperazine-1-carboxylate (2.8 g, 8.15 mmol) inDCM (20 mL) was added TFA (5 mL). The mixture was stirred at 20° C. for1 h. Concentrated and diluted with ethyl acetate. Adjusted pH to 7-8with sat. NaHCO₃ solution. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated to give the title product (1.98 g,crude). MS (ES+) C₈H₁₁BrN₄ requires: 242, found: 243 [M+H]⁺.

Step 3: Synthesis of 2-bromo-5-(4-isopropylpiperazin-1-yl)pyrazine

A mixture of 2-bromo-5-(piperazin-1-yl)pyrazine (458 mg, 1.88 mmol),2-iodopropane (479 mg, 2.82 mmol) and K₂CO₃ (518 mg, 3.76 mmol) in MeCN(10 mL) was stirred at 60° C. overnight. Concentrated and purified bysilica gel column (MeOH/EA=1:10) to give the title product (388 mg,yield 72%). MS (ES+) C₁₁H₁₇BrN₄ requires: 284, found: 285[M+H]⁺.

Step 4: Synthesis of tert-butyl4-(6-(5-(4-isopropylpiperazin-1-yl)pyrazin-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

A mixture of 2-bromo-5-(4-isopropylpiperazin-1-yl)pyrazine (350 mg, 1.22mmol), tert-butyl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(625 mg, 1.46 mmol), Na₂CO₃ (193 mg, 1.83 mmol) and Pd(t-Bu₃P)₂ (62.3mg, 122 μmol) in dioxane/water (20 mL) was purged with N₂, and thenstirred at 90° C. overnight under nitrogen. Concentrated and purified bysilica gel column (MeOH/EA=1:10) to give the title product (388 mg,yield 63%). MS (ES+) C₂₇H₃₈N₈O₂ requires: 506, found: 507 [M+H]⁺.

Step 5: Synthesis of6-(5-(4-isopropylpiperazin-1-yl)pyrazin-2-yl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazinehydrochloride

To a solution of tert-butyl4-(6-(5-(4-isopropylpiperazin-1-yl)pyrazin-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(388 mg, 765 μmol) in DCM (4 mL) was added HCl/dioxane (4 mL, 4 M). Themixture was stirred at 20° C. overnight and then concentrated to givethe title product (338 mg, crude). MS (ES+) C₂₂H₃₁ClN₈ requires: 406,found: 407 [M+H]⁺.

Step 6: Synthesis of ethyl4-(6-(5-(4-isopropylpiperazin-1-yl)pyrazin-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(Compound 448)

To a solution of6-(5-(4-isopropylpiperazin-1-yl)pyrazin-2-yl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazinehydrochloride (100 mg, 225 μmol) and DIPEA (87.0 mg, 675 μmol) in DCM(10 mL) was added ethyl chloroformate (48.8 mg, 450 μmol). The mixturewas stirred at 20° C. for 1 h and then concentrated and purified byPrep-HPLC to give the title product (30.0 mg, yield 28%). MS (ES+)C₂₅H₃₄N₈O₂ requires: 478, found: 479 [M+H]⁺.

Example 14. Synthesis of1-(4-(6-(4-(1-ethylpyrrolidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carbonyl)azetidine-3-carbonitrile(Compound 300) Step 1: Synthesis of tert-butyl4-(6-(4-(1-ethylpyrrolidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

A solution of 3-(4-bromophenyl)-1-ethylpyrrolidine (200 mg, 786 μmol) indioxane/water (5 mL) was added tert-butyl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(336 mg, 786 μmol), Pd(t-Bu₃P)₂ (40.1 mg, 78.6 μmol) and Cs₂CO₃ (763 mg,2.35 mmol) was degassed with nitrogen, and then heated at 60° C. underMW for 1 h. The reaction mixture was cooled to RT and concentrated. Theresidue was purified by flash chromatography to afford the titlecompound (300 mg, yield 80%). MS (ES+) C₂₈H₃₇N₅O₂, requires: 475, found:476[M+H]⁺.

Step 2: Synthesis of6-(4-(1-ethylpyrrolidin-3-yl)phenyl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazine

To a solution of tert-butyl4-(6-(4-(1-ethylpyrrolidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(300 mg, 630 μmol) in DCM (8 mL) was added TFA (5 mL). The reactionmixture was stirred at 20° C. for 18 h. The mixture was concentrated togive the title compound (230 mg, yield 97%). MS (ES+) C₂₈H₃₄N₆O₂,requires: 375, found: 376 [M+H]⁺.

Step 3: Synthesis ofl-(4-(6-(4-(1-ethylpyrrolidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carbonyl)azetidine-3-carbonitrile

To a solution of6-(4-(1-ethylpyrrolidin-3-yl)phenyl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazine(200 mg, 532 μmol) in DMF (5 mL) was added 4-nitrophenyl3-cyanoazetidine-1-carboxylate (131 mg, 532 μmol) and Na₂CO₃ (168 mg,1.59 mmol). The reaction mixture was stirred at 20° C. for 18 hrs. Waterwas added and extracted with DCM/MeOH(10/1). The mixture wasconcentrated to give a residue, which was purified by Prep-HPLC to givethe title compound (130 mg, yield 51%). MS (ES+) C₂₈H₃₃N₇O, requires:483, found: 484[M+H]⁺.

Example 15. Synthesis of(4-(6-(4-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(Compound 260) Step 1: Synthesis of 2-oxa-5,8-diazaspiro[3.5]nonane

To a mixture of tert-butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate(100 mg, 438 μmol) in DCM (3 mL) was added TFA ((1 mL). The reactionmixture was stirred at 25° C. for 16 h. NH₃ (7 N in MeOH) was added toadjust pH to 8-9. The reaction mixture was concentrated in vacuo toafford the title compound (56 mg, crude) as a white solid MS (ES+)C₆H₁₂N₂O requires: 128, found 129 [M+H]⁺.

Step 2: Synthesis of(4-(6-(4-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(Compound 260)

A mixture of 2-oxa-5,8-diazaspiro[3.5]nonane (30 mg, 234 μmol),(4-(6-(4-bromophenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(129 mg, 304 μmol), Pd[(t-Bu)₃P]₂ (11.9 mg, 23.4 μmol) and Na₂CO₃ (49.6mg, 468 μmol) in toluene (3 mL) was degassed with nitrogen and stirredat 100° C. for 16 h under N₂. LCMS showed the reaction was completed.Concentrated in vacuo, the residue was purified by Prep-HPLC to affordthe title compound (7.2 mg, yield 6%) as a yellow solid MS (ES+)C₂₇H₃₂N₆O₂ requires: 472, found 473 [M+H]⁺.

Example 16. Synthesis of2-(6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(7H)-one(Compound 157) Step 1: Synthesis of 1-(4-bromophenyl)-4-ethylpiperazine

A mixture of 1-(4-bromophenyl)piperazine (40 g, 165 mmol), bromoethane(17.9 g, 165 mmol) and triethylamine (16.6 g, 165 mmol) in THF (500 ml)was stirred at 60° C. overnight. The reaction was cooled to RT, dilutedwith EA and washed with water. The organic layer was concentrated togive the title compound (50 g, crude). MS (ES+) C₁₂H₁₇BrN₂ requires:268, found 269 [M+H]⁺.

Step 2: Synthesis of1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine

A mixture of 1-(4-bromophenyl)-4-ethylpiperazine (50 g, 185 mmol), KOAc(54.3 g, 554 mmol) and Pd(dppf)Cl₂ (13.5 g, 18.5 mmol) in dioxane (500mL) was purged with N₂ and stirred at 60° C. overnight. The reactionmixture was cooled, concentrated and purified by silica gel column(PE/EA=5/1 to EA) to give the title compound (40 g, 69.5%). MS (ES+)C₁₈H₂₉BN₂O₂ requires: 316, found 317 [M+H]⁺.

Step 3: Synthesis of6-bromo-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrrolo[1,2-b]pyridazine

To a mixture of 6-bromopyrrolo[1,2-b]pyridazin-4-ol (22.0 g, 103 mmol)and triethylamine (31.2 g, 309 mmol) in THF (100 mL) was added(2-(chloromethoxy)ethyl)trimethylsilane (20.5 g, 123 mmol) dropwise at0° C. The reaction mixture was stirred at 20° C. for 1 h. The mixturewas concentrated, diluted with EA and washed with water. The organiclayer was concentrated and purified by flash column chromatography(PE/EA=5:1) to afford the title compound (31 g, yield 87%) as a yellowoil MS (ES+) C₁₃H₁₉BrN₂O₂Si requires: 342, found 343 [M+H]⁺.

Step 4: Synthesis of6-(4-(4-ethylpiperazin-1-yl)phenyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrrolo[1,2-b]pyridazine

A mixture of6-bromo-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrrolo[1,2-b]pyridazine (5g, 14.5 mmol),1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine(5.94 g, 18.8 mmol), K₂CO₃ (6.0 g, 43.5 mmol) and Pd[(t-Bu)₃P]₂ (370 mg,725 μmol) in dioxane/water (30 mL, 4/1) was purged with N₂ and thenstirred at 70° C. for 4 h under N₂. The mixture was purified by flashcolumn chromatography (PE/EA=10:1 to 1:2) to afford the title compound(6 g, yield 91%) as a grey solid. MS (ES+) C₂₅H₃₆N₄O₂Si requires: 452,found 453 [M+H]⁺.

Step 5: Synthesis of6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-ol

To a mixture of6-(4-(4-ethylpiperazin-1-yl)phenyl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrrolo[1,2-b]pyridazine(8.0 g, 17.6 mmol) in dioxane (20 mL) was added HCl (4 N in dioxane, 40mL). The mixture was stirred at 25° C. for 1 h. The mixture wasconcentrated in vacuo to afford the title compound (4.77 g, crude) as ayellow solid. MS (ES+) C₁₉H₂₂N₄O requires: 322, found: 323 [M+H]⁺.

Step 6: Synthesis of6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonate

To a solution of6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-ol (3.0 g,9.30 mmol) in DCM (30 mL) at 0° C. was added triethylamine (2.82 g, 27.9mmol), followed by addition of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(3.96 g, 11.1 mmol). The reaction mixture was stirred at 0° C. for 2 h.The mixture was diluted with DCM and washed with brine. The organiclayer was evaporated and purified by flash column (PE:EA=5:1) to affordthe title compound (1.9 g, yield 45%) as a yellow solid MS (ES+)C₂₀H₂₁F₃N₄O₃S requires: 454, found 455 [M+H]⁺.

Step 7: Synthesis of2-(6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(7H)-one

A mixture of hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (30 mg, 214 μmol),6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonate (116 mg, 256 μmol) and triethylamine (64.9 mg,642 μmol) in NMP (2 mL) was stirred at 100° C. for 1 h. The mixture wasconcentrated and purified by Prep-HPLC to afford the title compound (4.0mg, yield 4%) as a white solid MS (ES+) C₂₆H₃₂N₆O requires: 444, found445 [M+H]⁺.

Example 17. Synthesis ofcyclopropyl(2-(difluoromethyl)-4-(6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 403) Step 1: Synthesis of 2-(difluoromethyl)piperazine

To a solution of tert-butyl 3-(difluoromethyl)piperazine-1-carboxylate(30 mg, 0.127 mmol) in dioxane (2.0 mL) was added HCl/dioxane (4 N, 1.0mL). The reaction solution was stirred at 25° C. for 1 h. The reactionmixture was concentrated. The residue was used in next step directlywithout any further purification.

Step 2: Synthesis of4-(3-(difluoromethyl)piperazin-1-yl)-6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazine

A mixture of6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yltrifluoromethanesulfonate (60 mg, 0.13 mmol) and2-(difluoromethyl)piperazine (17 mg, 0.13 mmol) and triethylamine (40mg, 0.40 mmol) in NMP (3 mL) was stirred at 100° C. for 2 h. Thereaction solution was used in next step directly without any furtherpurification. MS (ES+) C₂₄H₃₀F₂N₆ requires: 440, found 441 [M+H]⁺.

Step 3: Synthesis ofcyclopropyl(2-(difluoromethyl)-4-(6-(4-(4-ethylpiperazin-1-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 403)

To above reaction mixture was added triethylamine (40 mg, 0.40 mmol) andcyclopropanecarbonyl chloride (27 mg, 0.26 mmol). The mixture wasstirred at RT for 2 h. The reaction mixture was concentrated andpurified by Prep-HPLC to give the title product as a yellow solid (3.8mg, yield 7.6%). MS (ES+) C₂₈H₃₄F₂N₆O requires: 508, found 509 [M+H]⁺.

Example 18. Synthesis ofcyclopropyl(4-(6-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 111)

Step 1: Synthesis of4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)benzaldehyde

A mixture ofcyclopropyl(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(250 mg, 0.63 mmol), 4-bromobenzaldehyde (120 mg, 0.65 mmol), sodiumcarbonate (200 mg, 1.89 mmol) and Pd(t-Bu₃P)₂ (65 mg, 0.13 mmol) indioxane/water (15 mL) was purged with N₂, and then stirred at 75° C. for3 h. Cooled to RT and diluted with EtOAc. The organic layer was washedwith water and brine, concentrated and purified by flash column(PE/EtOAc=10/1 to 5/1) to give the title product (180 mg, crude). MS(ES+) C₂₂H₂₂N₄O₂ requires: 374, found 375 [M+H]⁺.

Step 2: Synthesis ofcyclopropyl(4-(6-(4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 111)

To a solution of4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)benzaldehyde(180 mg, 0.48 mmol) in t-BuOH (20 mL) was added potassium carbonate (200mg, 1.44 mmol) and iodine (122 mg, 0.48 mmol). The reaction mixture washeated at 70 degrees for 2 h. Quenched by sat. aq. Na₂S₂O₃ (20 mL) anddiluted with EtOAc. The organic layer was washed with water and brine,concentrated and purified by column (DCM/MeOH=20/1 to 5/1) to give thetitle product (98.99 mg, 49.7%). MS (ES+) C₂₄H₂₆N₆O requires: 414, found415 [M+H]⁺.

Example 19. Synthesis ofcyclopropyl(4-(6-(4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 121) Step 1: Synthesis of(4-(6-(4-aminophenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone

A mixture of(4-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(250 mg, 0.72 mmol), 4-aminophenylboronic acid (150 mg, 1.08 mmol),K₂CO₃ (300 mg, 2.16 mmol) and Pd(dppf)Cl₂ (100 mg) in 1,4-dioane (20 mL)and water (4 mL) was purged with N₂, and then stirred at 100° C. for 6h. Cooled to RT and diluted with DCM. The organic layer was washed withwater and brine, concentrated and purified by flash column(DCM/MeOH=100/1 to 20/1) to give the title product (130 mg, yield: 50%).MS (ES+) C₂₁H₂₃N₅O requires: 361, found 362 [M+H]⁺.

Step 2: Synthesis of dimethyl4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)phenylcarbonimidodithioate

To a solution of(4-(6-(4-aminophenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)(cyclopropyl)methanone(100 mg, 0.28 mmol) in DMF (6 mL) was added CS₂ (1 mL). The reactionmixture was added 6 ml of NaOH in water (1 N) and stirred at RT for 30min. The reaction mixture was added methyl iodide (0.3 ml) and stirredovernight at RT. The mixture was extracted with DCM. The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedto give the title product (120 mg, crude). MS (ES+) C₂₄H₂₇N₅OS₂requires: 465, found 466 [M+H]⁺.

Step 3: Synthesis ofcyclopropyl(4-(6-(4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazin-1-yl)methanone(Compound 121)

A mixture of dimethyl4-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)phenylcarbonimidodithioate(120 mg, crude) and ethane-1,2-diamine (300 mg) in DMF (5 mL) was heatedto 120° C. for 10 h. The reaction mixture was concentrated andpurification by Pre-HPLC to give the title product as a white solid(48.2 mg, yield 40.2%). MS (ES+) C₂₄H₂₇N₇O requires: 429, found 430[M+H]⁺.

Example 20. Synthesis of ethyl4-(6-(2-fluoro-4-(1-isopropyl-4-methoxypiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(Compound 701) Step 1: Synthesis of4-(piperazin-1-yl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolo[1,2-b]pyridazine

A mixture of tert-butyl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(100 g, 0.234 mol) in DCM (200 mL) was added HCl in dioxane (584 mL,2.34 mol) at 15° C. for 16 hrs. The reaction mixture was cooled to RTand concentrated to afford the title product (100 g, crude) as a yellowsolid. MS (ES+) C₁₇H₂₅BN₄O₂ requires: 328, found: 329 [M+H]+.

Step 2: Synthesis of ethyl4-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

4-(piperazin-1-yl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolo[1,2-b]pyridazine,2TFA (917 mg, 1.45 mmole) was dissolved in 7 mL dichloromethane andHunig's base (1.0 mmole, 5.8 mmole) was added followed by ethylchloroformate (167 uL, 1.7 mmole) and the reaction mixture allowed tostir overnight at room temperature. The reaction mixture was evaporatedexhaustively and then the residue was preloaded onto silica gel andsubjected to flash chromatography using a gradient of 0 to 100% ethylacetate/hexane. Pure fractions were combined and evaporated to give 403mg (58%) of the title compound as a pale yellow foam.

Step 3: Synthesis of ethyl4-(6-(2-fluoro-4-(1-isopropyl-4-methoxypiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(Compound 701)

Ethyl4-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(106 mg, 0.22 mmole),4-(4-bromo-3-fluorophenyl)-1-isopropyl-4-methoxypiperidine (70 mg, 0.21mmole), palladium (II) acetate (1.0 mg, 2 mol %), SPhos (3.5 mg, 4 mol%), and potassium carbonate (88 mg, 0.64 mmole) were combined in a vialand purged with nitrogen. Acetonitrile (0.8 mL) and water (0.4 mL) wereadded and then the reaction was heated to 100 degrees in an oil bath for3 hours. The reaction mixture was diluted with ethyl acetate and thenfiltered through celite and transferred to a separatory funnel. Theorganic layer was washed with brine and dried over sodium sulfate.Filtration and evaporation gave the crude product, which was subjectedto flash chromatography using a gradient of 0 to 10%methanol/dichloromethane containing 1% ammonium hydroxide. Purefractions were combined and evaporated to give 96 mg (87%) of the titlecompound as a tan-colored foam.

Example 21. Synthesis of3-hydroxy-2-(4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carbonyloxy)propanoic acid(Compound 847) Step 1. Synthesis of benzyl 2,3-dihydroxypropanoate

To a solution of 2,3-dihydroxypropanoic acid (10.0 g, 18.8 mmol, 20% aq)in DMF (20 mL) was added (bromomethyl)benzene (8.0 g, 47.1 mmol) andK₂CO₃ (6.5 g, 47.1 mmol). The resulting mixture was stirred at roomtemperature for 48 h. LC-MS showed that the reaction was completed. Thesolvent was evaporated. The residue was dissolved in EtOAc and washedwith brine. The organic layer was dried over Na₂SO₄, filtered andevaporated. The crude product was purified by flash chromatography onsilica gel eluting with EtOAc/petroleum ether (3:1) to give the titlecompound (1.7 g, 46% yield) as a colorless oil.

Step 2. Synthesis of benzyl3-(tert-butyldiphenylsilyloxy)-2-hydroxypropanoate

To a solution of benzyl 2,3-dihydroxypropanoate (1.7 g, 8.6 mmol) in DMF(10 mL) was added tert-butylchlorodiphenylsilane (2.6 g, 9.5 mmol) andimidazole (1.2 g, 17.2 mmol). The resulting mixture was stirred at roomtemperature for 16 hours; LC-MS showed that the reaction was completed.Water was added and extracted with DCM. The organic was washed withbrine, dried over Na₂SO₄ and concentrated to afford crude product whichwas purified by flash chromatography on silica gel eluting with PE/EA(3:1) to give the title product (510 mg, 14% yield) as a colorless oil.

Step 3. Synthesis of1-(benzyloxy)-3-(tert-butyldiphenylsilyloxy)-1-oxopropan-2-yl4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

To a solution of benzyl3-(tert-butyldiphenylsilyloxy)-2-hydroxypropanoate (510 mg, 1.2 mmol) inDCM (10 mL) was added CDI (194 mg, 1.2 mmol). The solution was stirredat room temperature for 6 h.

In another flask,6-(4-(1-isopropylpiperidin-4-yl)phenyl)-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazine (322 mg, 0.8 mmol) was dissolved in DCM (5 mL) and TEA(244 mg, 2.4 mmol) was added thereto. The above solution of benzyl3-(tert-butyldiphenylsilyloxy)-2-hydroxypropanoate and CDI was added thesolution. The mixture was stirred at room temperature for 16 hours;LC-MS showed that the reaction was completed. Water was added andextracted with EtOAc. The organic was washed with brine, dried overNa₂SO₄ and concentrated to afford crude product, which was purified bysilica gel chromatography eluting with PE/EA (1:1) to give the titlecompound (310 mg, 45% yield) as a light yellow solid.

Step 4. Synthesis of 1-(benzyloxy)-3-hydroxy-1-oxopropan-2-yl4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

To a solution of1-(benzyloxy)-3-(tert-butyldiphenylsilyloxy)-1-oxopropan-2-yl4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(250 mg, 0.29 mmol) in THF (5 mL) was added TBAF (2.0 mL, 1.0 M). Thesolution was heated at 70° C. for 6 hours. The reaction mixture wasconcentrated and subjected to silica gel eluting with DCM/MeOH (10:1) togive the title compound (80 mg, 44% yield) as a light yellow solid.

Step 5. Synthesis of3-hydroxy-2-(4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carbonyloxy)propanoic acid

To a solution of 1-(benzyloxy)-3-hydroxy-1-oxopropan-2-yl4-(6-(4-(1-isopropylpiperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(80 mg, 0.12 mmol) in MeOH (5 mL) was added Pd/C (50 mg, 10% wet). Thesuspension was hydrogenated with H₂ balloon at room temperature for 16hours. Filtered off and the filtrate was evaporated to afford crudeproduct which was purified by Prep-HPLC to give the title compound (5.3mg, 8% yield) as a light white solid.

Example 22. Synthesis of 1,3-dihydroxypropan-2-yl4-(6-(4-(piperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate (Compound 789)Step 1. Synthesis of 2-phenyl-1,3-dioxan-5-yl4-(6-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

To a solution of 2-phenyl-1,3-dioxan-5-ol (327 mg, 1.82 mmol) in DCM (5mL) was added CDI (295 mg, 1.82 mmol). The resulting mixture was stirredat room temperature for 6 h. In another flask, tert-butyl4-(4-(4-(piperazin-1-yl)pyrrolo-[1,2-b]pyridazin-6-yl)phenyl)piperidine-1-carboxylate(420 mg, 0.91 mmol) was dissolved in DCM (5 mL) and TEA (278 mg, 2.73mmol) was added thereto. The above solution of 2-phenyl-1,3-dioxan-5-oland CDI was added into the solution. The reaction mixture was stirred atroom temperature for 16 hours where LC-MS showed that the reaction wascompleted. Water was added and extracted with EtOAc. The organic layerswere washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by PE/EA (2:1) to give the title compound (340 mg, 56%) asa yellow powder.

Step 2. Synthesis of 1,3-dihydroxypropan-2-yl4-(6-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

To a solution of 2-phenyl-1,3-dioxan-5-yl4-(6-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(310 mg, 0.46 mmol) in MeOH (10 mL) was added Pd(OH)₂/C (100 mg). Thesuspension was hydrogenated with hydrogen balloon at room temperaturefor 16 hours. LC-MS showed that the reaction was completed. Thesuspension was then filtered and the solvent was removed under reducedpressure to give the title product (210 mg, 78% yield) as a yellowsolid.

Step 3. Synthesis of 1,3-dihydroxypropan-2-yl4-(6-(4-(piperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

To a solution of 1,3-dihydroxypropan-2-yl4-(6-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(210 mg, 0.36 mmol) in DCM (5 mL) was added TFA (2.5 mL) at 0° C. Theresulting mixture was stirred at room temperature for 3 hours. LC-MSindicated that the reaction was completed. The resulting mixture wasevaporated to dryness to afford crude product which was purified byPrep-HPLC to give the title compound as a white powder.

Example 23. Synthesis of (S)-oxetan-3-yl4-(6-(4-(1-isopropylpiperidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(Compound 631) Step 1: Synthesis of4-(piperazin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazinehydrochloride

To a solution of tert-butyl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(7 g, 16.3 mmol) in dioxane (200 mL) was added HCl/dioxane (4 M, 16 mL).The reaction mixture was stirred at 20° C. overnight. The resultingmixture was concentrated to give the title compound as a yellow solid (9g, crude). MS (ES+) C₁₇H₂₆BClN4O₂ requires: 328, found: 329 [M+H]+.

Step 2: Synthesis of 4-nitrophenyl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

To a solution of4-(piperazin-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazinehydrochloride (7 g, 19.1 mmol) in dichloromethane (DCM) (100 mL) wasadded triethylamine (TEA) (11.6 g, 115 mmol) and 4-nitrophenylcarbonochloridate (4.62 g, 23 mmol). The mixture was stirred at roomtemperature (RT) for 4 h. The solution was concentrated to give aresidue, which was purified by flash chromatography to afford the titlecompound (7 g, 85%). MS (ES+) C₂₄H₂₈BN₅O₆ requires: 493, found:494[M+H]+.

Step 3: Synthesis of oxetan-3-yl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

To a solution of oxetan-3-ol (1.56 g, 21.1 mmol) in tetrahydrofuran(THF) (200 mL) at 0° C. was added 60% NaH (2.26 g, 56.4 mmol). Themixture was stirred at 25° C. for 1 h, followed by 4-nitrophenyl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(7 g, 14.1 mmol). The reaction mixture was stirred at 25° C. for another5 h. The reaction was quenched with NH₄Cl solution and extracted withethyl acetate. Combined, dried and concentrated to give the titlecompound (3.5 g, 71%). MS (ES+) C₂₁H₂₉BN₄O₅ requires: 428, found:429[M+H]+.

Step 4: Synthesis of (S)-oxetan-3-yl4-(6-(4-(1-isopropylpiperidin-3-yl)phenyl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate

A solution of oxetan-3-yl4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylate(3 g, 7.00 mmol) in dioxane/water (20 mL, 10/1) was added(S)-3-(4-bromophenyl)-1-isopropylpiperidine (1.77 g, 6.30 mmol),Pd(dppf)Cl₂ (511 mg, 700 μmol) and K₂CO₃ (2.89 g, 21.0 mmol) wasdegassed with nitrogen and heated at 90° C. for 5 h. The reactionmixture was cooled to RT and concentrated to give a residue, which waspurified by flash chromatography to afford the title compound (1.5 g,43%)

Example 24. Building Block Synthesis A. Synthesis of1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of bromocyclopentane (1.0 g, 6.71 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.32 g,6.84 mmol) and Cs₂CO₃ (6.54 g, 20.1 mmol) in CH₃CN (50 mL) was refluxedovernight. The mixture was cooled, concentrated and purified by flashcolumn chromatography (PE:EA=5:1) to give the title compound as a whitesolid (1.5 g, yield 85.7%). MS (ES+) C₁₄H₂₃BN₂O₂ requires: 262, found263 [M+H]⁺.

B. Synthesis of1-(2,2-difluoroethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineStep 1: Synthesis of 2,2-difluoroacetaldehyde

To a solution of 2,2-difluoroethanol (2.0 g, 24.3 mmol) in DMF (20 mL)was added Dess-Martin periodinane (25.7 g, 60.7 mmol) in portions at 0°C. The solution was stirred at RT for 6 h. After that, the solution wasused directly for the next reaction.

Step 2: Synthesis of 1-(4-bromophenyl)-4-(2,2-difluoroethyl)piperazine

Above solution (24.3 mmol, assumed) in DMF was diluted with DCM (30 mL)and CH₃OH (30 mL). 1-(4-Bromophenyl)piperazine (6.0 g, 24.9 mmol) andacetic acid (1.49 g, 24.9 mmol) was added, followed by addition ofsodium cyanoborohydride (2.34 g, 37.3 mmol) at 0° C. The solution wasstirred at RT for 12 h. After that, the solution was cooled to 0° C.,quenched with NaHCO₃ (aq) and brine, and diluted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, concentrated andpurified by flash column (PE/EtOAc=6/1) to get the title compound as ayellow solid (400 mg, 5%). MS (ES+) C₁₂H₁₅BrF₂N₂ requires: 304, found305 [M+H]⁺.

Step 3: Synthesis of1-(2,2-difluoroethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine

A mixture of 1-(4-bromophenyl)-4-(2,2-difluoroethyl)piperazine (400 mg,1.31 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(497 mg, 1.96 mmol), potassium acetate (385 mg, 3.93 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (191 mg, 262mmol) in dioxane (20 mL) was purged with N₂, and then stirred at 80° C.for 16 h. After that, the mixture was cooled, concentrated and purifiedby flash column (PE/EtOAc=5/1) to get the title compound as a whitesolid (350 mg, 76%). MS (ES+) C₁₈H₂₇BF₂N₂O₂ requires: 352, found 353[M+H]⁺.

C. Synthesis of 1-(4-bromophenyl)-2-(difluoromethyl)piperazine Step 1:Synthesis of tert-butyl4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate

A mixture of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (5 g,23.1 mmol), (bromomethyl)benzene (4.73 g, 27.7 mmol) and triethylamine(4.67 g, 46.2 mmol) in acetonitrile (40 mL) was stirred at 80° C.overnight. The reaction solution was cooled, concentrated and purifiedby silica gel chromatograph (EA:PE=1:5) to give the title product (6.0g, yield: 85%) as colorless oil. MS (ES+) C₁₇H₂₆N₂O₃ requires: 306,found: 307 [M+H]⁺.

Step 2: Synthesis of tert-butyl4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate

A solution of oxalyl chloride (1.98 g, 15.6 mmol) in DCM (10 mL) wasadded DMSO (1.52 g, 19.5 mmol) in DCM (10 mL) at −78° C. The mixture wasstirred for 15 min, followed by addition of tert-butyl4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (4.00 g, 13.0 mmol).The resulting mixture was stirred at RT for 2 h, followed by addition ofEt₃N. LC-MS showed full conversion. The reaction mixture was dilutedwith DCM, washed with water and brine, and dried over sodium sulfate.The organic layer was concentrated to afford the title compound (4.00 g,crude) as a yellow oil, which was used in the next step without furtherpurification. MS (ES+) C₁₇H₂₄N₂O₃ requires: 304, found: 305 [M+H]⁺.

Step 3: Synthesis of tert-butyl4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate

A mixture of tert-butyl 4-benzyl-3-formylpiperazine-1-carboxylate (4.00g, 13.1 mmol) in DCM (10 mL) was added diethylaminosulfurtrifluoride(3.45 mL, 26.2 mmol) at 0° C. The reaction mixture was stirred at 0° C.for 2 h. LC-MS showed full conversion. The reaction solution was pouredinto ice water and extracted with DCM. The organic layer was washed withwater and brine, dried over sodium sulfate, concentrated and purified bysilica gel chromatograph (EA:PE=1:5) to give the title product (1.40 g,yield 33%) as a light yellow oil. MS (ES+) C₁₇H₂₄F₂N₂O₂ requires: 326,found: 327 [M+H]⁺.

Step 4: Synthesis of tert-butyl3-(difluoromethyl)piperazine-1-carboxylate

A mixture of tert-butyl4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate (1.20 g, 3.67 mmol)in methanol (10 mL) was added Pd/C (388 mg). The suspension was stirredat RT overnight under H₂ (balloon). LC-MS showed full conversion. Thereaction mixture was filtered through a pad of Celite. The filtrate wasconcentrated to give the title product (800 mg, crude) as a light yellowoil, which was used in the next step without further purification.

Step 5: Synthesis of tert-butyl4-(4-bromophenyl)-3-(difluoromethyl)piperazine-1-carboxylate

A mixture of tert-butyl 3-(difluoromethyl)piperazine-1-carboxylate (250mg, 1.05 mmol), 1-bromo-4-iodobenzene (1.48 g, 5.25 mmol),bis(tri-t-butylphosphine)palla dium (268 mg, 525 umol) and sodiumtert-butoxide (201 mg, 2.10 mmol) in toluene (20 mL) was purged with N₂,and then stirred at 60° C. for 15 h. LCMS showed full conversion. Thereaction mixture was concentrated. The residue was purified by silicagel chromatograph (EA:PE=1:10 to EA:PE=1:1) to give the title product(310 mg, yield 75%) as a colorless oil. MS (ES+) C₁₆H₂₁BrF₂N₂O₂requires: 390, found: 391, [M+H]⁺.

Step 6: Synthesis of 1-(4-bromophenyl)-2-(difluoromethyl)piperazine

A mixture of tert-butyl4-(4-bromophenyl)-3-(difluoromethyl)piperazine-1-carboxylate (150 mg,383 μmol) in HCl/dioxane (4 M, 2 mL) was stirred at RT for 1.5 h. LCMSshowed full conversion. The reaction mixture was concentrated andpurified by Prep-HPLC to give the title product (80 mg, yield 72%) ascolorless oil. MS (ES+) C₁₁H₁₃BrF₂N₂ requires: 290, found: 291[M+H]⁺.

D. Synthesis of tert-butyl3-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate Step 1: Synthesis oftert-butyl 3-(4-bromophenyl)-3-hydroxypiperidine-1-carboxylate

A solution of 1-bromo-4-iodobenzene (1.0 g, 3.53 mmol) in THF (20 mL)was cooled to 78° C., followed by addition of n-BuLi (2.5 N in hexane,1.4 mL, 3.53 mmol). After 15 minutes, tert-butyl3-oxopiperidine-1-carboxylate (703 mg, 3.53 mmol) in THF (5 mL) wasadded slowly. The reaction solution was stirred for 2 h at −78° C.,allowed to warm up to 0° C., and quenched using saturated aqueous NH₄Cland extracted with EA. The organic layer was concentrated and purifiedby flash column (silica gel, PE:EA=3:1) to give the title product (0.8g, yield 64%) as a colorless oil. MS (ES+) C₁₆H₂₂BrNO₃ requires: 355,found 356 [M+H]⁺.

Step 2: Synthesis of tert-butyl3-(4-bromophenyl)-3-fluoropiperidine-1-carboxylate

To a solution of tert-butyl3-(4-bromophenyl)-3-hydroxypiperidine-1-carboxylate (3.0 g, 8.42 mmol)in DCM (30 mL) was added Dast (2.0 g, 12.6 mmol) at 0° C. The reactionmixture was stirred at RT for 5 h. The mixture was diluted with DCM,washed with aq. NaHCO₃ and brine, evaporated and purified by flashcolumn (silica gel, PE:EA=5:1) to give the title product (1.5 g, yield50%) as a colorless oil. MS (ES+) C₁₆H₂₁BrFNO₂ requires: 357, found 358[M+H]⁺.

E. Synthesis of tert-butyl3-(4-bromophenyl)-4-fluoropyrrolidine-1-carboxylate Step 1: Synthesis oftert-butyl 3-(4-bromophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

A mixture of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(1.0 g, 3.38 mmol), 1-bromo-4-iodobenzene (1.91 g, 6.76 mmol),Pd(dppf)Cl₂ (247 mg, 338 μmol) and K₂CO₃ (932 mg, 6.76 mmol) indioxane/water (5 mL, 4/1) was purged with N₂ and stirred at 80° C. for16 h under N₂. The mixture was cooled and concentrated in vacuo. Theresidue was purified by flash column chromatography (PE/EA=10:1) toafford the title compound (800 mg, yield 73%) as a white solid MS (ES+)C₁₅H₁₈BrNO₂ requires: 323, found 324[M+H]⁺.

Step 2: Synthesis of tert-butyl3-(4-bromophenyl)-4-hydroxypyrrolidine-1-carboxylate

A solution of BH₃ (1 N in THF, 21.5 mL, 21.5 mmol) was added to astirring solution of tert-butyl3-(4-bromophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.4 g, 4.31mmol) in THF (20 mL) at 0° C. After stirred at RT for 4 h, the mixturewas cooled to 0° C., followed by addition of NaOH aqueous (4 N, 6.45 mL,25.8 mmol). After 10 min, H₂O₂ (2.92 g, 25.8 mmol) was added. Theresulting mixture was allowed to warm up to RT and stirred for 90 min.Monitored by LC-MS. Quenched by water and extracted with ethyl acetate.The organic layer was concentrated and purified by flash columnchromatography (PE/EA=10:1 to 1:1) to afford the title compound (1.3 g,yield 88%) as a light oil MS (ES+) C₁₅H₂₀BrNO₃ requires: 341, found 342[M+H]⁺.

Step 3: Synthesis of tert-butyl3-(4-bromophenyl)-4-fluoropyrrolidine-1-carboxylate

To a mixture of tert-butyl3-(4-bromophenyl)-4-hydroxypyrrolidine-1-carboxylate (500 mg, 1.46 mmol)in DCM (10 mL) was added dropwise DAST (1.17 g, 7.29 mmol) at −78° C.The mixture was stirred at 25° C. for 2 h. Monitored by LC-MS. Dilutedwith DCM and quenched with saturated NaHCO₃ solution. The organic layerwas separated and concentrated in vacuo to afford the title compound(400 mg, crude) as a yellow oil. MS (ES+) C₁₅H₁₉BrFNO₂ requires: 343,found: 344 [M+H]+.

F. Synthesis of 4-(4-bromophenyl)-4-methoxypiperidine Step 1: Synthesisof tert-butyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

To a solution of 1-bromo-4-iodobenzene (12 g, 42.6 mmol) in THF (60 mL)at −78° C. was added BuLi (20 mL, 2.4 M in hexane) dropwise. Thesolution was stirred at −78° C. for 2 h. A solution of tert-butyl4-oxopiperidine-1-carboxylate (8.5 g, 42.4 mmol) in THF (20 mL) wasadded dropwise. The resulting solution was stirred at −78° C. for 1 h.The reaction was quenched carefully by addition of water and extractedwith EtOAc. The organic layer was washed with water and brine,concentrated and purified by flash column (PE/EtOAc=10/1 to 3/1) to givethe title product (12.6 g, yield 83.4%). MS (ES+) C₁₆H₂₂BrNO₃ requires:355, found 282 [M-73]⁺.

Step 2: Synthesis of tert-butyl4-(4-bromophenyl)-4-methoxypiperidine-1-carboxylate

To a solution of tert-butyl4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (178 mg, 499 μmol)in dry DMF (2 mL) was added NaH (26 mg, 0.646 mmol) at 0° C. The mixturewas stirred at 0° C. for 1 h. Iodomethane (106 mg, 0.746 mmol) wasadded. The mixture was stirred at RT overnight. The reaction wasquenched carefully by addition of water, extracted with EtOAc, washedwith water and brine, concentrated and purified by flash column(PE/EtOAc=10/1 to 5/1) to give the title product (160 mg, yield 86.5%).MS (ES+) C₁₇H₂₄BrNO₃ requires: 369, found 282 [M+H-88]⁺.

Step 3: Synthesis of 4-(4-bromophenyl)-4-methoxypiperidine

To a solution of tert-butyl4-(4-bromophenyl)-4-methoxypiperidine-1-carboxylate (740 mg, 1.99 mmol)in dioxane (4 mL) was added HCl (4 M in dioxane, 3 mL). The resultingsolution was stirred at RT overnight. The solvent was removed in vacuoto afford the title product (690 mg, crude). MS (ES+) C12H₁₆BrNOrequires: 269, found 270 [M+H]⁺.

Step 4: Synthesis of 4-(4-bromophenyl)-4-methoxypiperidine

To a solution of 4-(4-bromophenyl)-4-methoxypiperidine (1 g, 3.70 mmol)in CH₃CN (50 mL) was added K₂CO₃ (1.53 g, 11.1 mmol) and 2-bromopropane(2.27 g, 18.5 mmol). The resulting mixture was stirred at 80° C. for 5h. The solvent was removed in vacuo. The residue was purified by flashcolumn (PE/EtOAc=10/1 to 5/1) to afford the title product (1.06 g, yield91.8%). MS (ES+) C₁₅H₂₂BrNO requires: 311, found 312 [M+H]⁺.

G. Synthesis of1-isopropyl-4-methoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidineStep 1: Synthesis of tert-butyl4-methoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate

A mixture of tert-butyl4-(4-bromophenyl)-4-methoxypiperidine-1-carboxylate (200 mg, 540 μmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (178 mg, 702μmol), Pd(dppf)Cl₂ (39.5 mg, 54.0 μmol) and K₂CO₃ (105 mg, 1.08 mmol) indioxane (10 mL) was stirred at 65° C. for 4 h. The reaction mixture wasconcentrated and purified by silica gel chromatography (PE:EA=10:1 to5:1) to give the title product (158 mg, yield: 70%) as a yellow solid.MS (ES+) C₂₃H₃₆BNO₅ requires: 417, found 418 [M+H]⁺.

Step 2: Synthesis of4-methoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine

A mixture of tert-butyl4-methoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate(6 g, 14.3 mmol) and HCl/dioxane (30 mL) in DCM (30 mL) was stirred atRT for 1 h. The reaction mixture was concentrated to give the titleproduct (4.6 g, crude) as a light yellow solid, which was used for thenext step without purification. MS (ES+) C₁₈H₂₈BNO₃ requires: 317, found318 [M+H]⁺.

Step 3: Synthesis of 1-isopropyl-4-methoxy-4-(4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl)piperidine

A mixture of4-methoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine(4.5 g, 14.1 mmol), 2-iodopropane (3.58 g, 21.1 mmol) and K₂CO₃ (5.84 g,42.3 mmol) in acetonitrile (50 mL) was stirred at 85° C. for 2 h. Thereaction mixture was concentrated and purified by silica gelchromatography (DCM:MeOH=15:1) to give the title product (4.8 g, yield:95%) as a light yellow solid. MS (ES+) C₂₁H₃₄BNO₃ requires: 359, found360 [M+H]⁺.

H. Synthesis of tert-butyl4-(3-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylateStep 1: Synthesis of 1,4-dibromo-2-(difluoromethoxy)benzene

To a solution of 2,5-dibromophenol (1.5 g, 6.0 mmol) in DMF/water (30mL/10 mL) was added sodium 2-chloro-2,2-difluoroacetate (2.3 g, 15.0mmol) and Cs₂CO₃ (3.9 g, 12.0 mmol) at RT. The resulting mixture wasstirred at 100° C. for 3 h. Quenched with water and extracted withEtOAc. The combined organic layer was washed with brine, dried overNa₂SO₄, and concentrated to dryness. The residue was purified by flashchromatography on silica gel eluting with PE/EtOAc (5:1) to give thetitle compound (1.2 g, yield 67%) as a light yellow powder. MS (ES+)C₇H₄Br₂F₂O requires: 300, found 301 [M+H]⁺ (weak ion mass).

Step 2: Synthesis of tert-butyl4-(4-bromo-3-(difluoromethoxy)phenyl)piperazine-1-carboxylate

To a solution of 1,4-dibromo-2-(difluoromethoxy)benzene (500 mg, 1.66mmol) and tert-butyl piperazine-1-carboxylate (309 mg, 1.66 mmol) in DMF(20 mL) was added Pd₂(dba)₃ (155 mg, 0.17 mmol), XantPhos (98 mg, 0.17mmol) and Cs₂CO₃ (1.6 g, 5.0 mmol) at RT under nitrogen. The resultingmixture was stirred at 90° C. for 1 h under Microwave. LC-MS showed thatthe reaction was completed. Quenched with water and extracted withEtOAc. The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated to dryness. The residue was purified by flashchromatography on silica gel eluting with PE/EtOAc (3:1 to 1:1) to givethe title compound (370 mg, yield 55%) as while solid. MS (ES+)C₁₆H₂₁BrF₂N₂O₃ requires: 406, found 351 [M+H-56]⁺.

Step 3: Synthesis of tert-butyl4-(3-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-bromo-3-(difluoromethoxy)phenyl)piperazine-1-carboxylate (320 mg,0.78 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (309 mg,1.66 mmol) in dioxane (10 mL) was added Pd(dppf)Cl₂ (63 mg, 0.078 mmol)and KOAc (229 mg, 2.34 mmol) at RT under nitrogen. The resulting mixturewas stirred at 90° C. for 6 h under nitrogen; LC-MS showed that thereaction was completed. Quenched with water and extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated to dryness to afford crude product, which was purifiedby flash chromatography on silica gel eluting with PE/EtOAc (10:1 to3:1) to give the title compound (260 mg, yield 73%) as while solid. MS(ES+) C22H₃₃BF₂N₂O₅ requires: 454, found 399 [M+H−56]⁺.

I. Synthesis of 2-(4-chlorophenyl)-1-isopropyl-2-methylpyrrolidine

Step 1: Synthesis of tert-butyl2-(4-chlorophenyl)-2-methylpyrrolidine-1-carboxylate

5-(4-chlorophenyl)-3,4-dihydro-2H-pyrrole (2.00 g, 11.1 mmole) wasdissolved in 33 mL dry THF and cooled to −78° C. Boron trifluoridediethyletherate (2.8 mL, 22.3 mmole) was added dropwise and stirred at−78° C. for 40 minutes and then 0.5M methyllithium in ether (13.9 mL,22.3 mmole) was added dropwise and then allowed to warm slowly to roomtemperature overnight. The reaction mixture was quenched with water anddiluted with ethyl acetate. The reaction mixture was acidified with 1MHCl and then transferred to a separatory funnel. The aqueous layer wasthen made basic to pH-12-13 with 6M NaOH and then extracted with ethylacetate (×2) and combined organics washed with brine and dried oversodium sulfate. Filter and evaporate to give the crude product, whichconsisted of desired product and the starting material. The two weredifficult to separate by chromatography so were converted to the Bocprotected product to facilitate separation: The crude product wasdissolved in 30 mL dichloromethane and then Boc anhydride (1.74 g, 8.0mmole) was added as a solution in 5 mL dichloromethane, followed by DMAP(100 mg, 0.8 mmole) and the mixture stirred at room temperatureovernight. The reaction mixture was evaporated and then subjected toflash chromatography (0 to 40% ethyl acetate/hexane, collecting allfractions due to low UV activity). Pure fractions combined andevaporated to give 920 mg (28%) of the title compound as a colorless oilthat crystallized on standing.

Step 2: Synthesis of 2-(4-chlorophenyl)-1-isopropyl-2-methylpyrrolidine

tert-Butyl 2-(4-chlorophenyl)-2-methylpyrrolidine-1-carboxylate (915 mg,3.1 mmole) was dissolved in 12 mL dichloromethane and trifluoroaceticacid (3.6 mmole, 46.4 mmole) was added and stirred at room temperaturefor 2 hours. The reaction mixture was evaporated exhaustively and thenthe residue partitioned between dichloromethane and 1M NaOH. The organiclayer was dried over sodium sulfate, filtered and evaporated to give 610mg (100%) of 2-(4-chlorophenyl)-2-methylpyrrolidine as a viscous orangeoil. This material was then dissolved in 10 mL acetonitrile in aheavy-walled pressure vessel and potassium carbonate (646 mg, 4.7 mmole)was added followed by 2-iodopropane (374 uL, 3.7 mmole). The reactionmixture was heated to 90° C. for 3 days and then diluted with ethylacetate. The reaction was filtered through celite and evaporated. Thecrude product was subjected to flash chromatography using an Isco aminecolumn, gradient of 0 to 30% ethyl acetate/hexane. Pure fractions werecombined and evaporated to give 509 mg (69%) of the desired product as apale yellow oil.

J. Synthesis of benzyl4-(4-bromophenyl)-4-fluoropiperidine-1-carboxylate

Step 1: Synthesis of benzyl4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

Benzyl 4-oxopiperidine-1-carboxylate (937 mg, 4.0 mmole) and1,4-dibromobenzene (790 mg, 3.4 mmole) were dissolved in 15 mL THF andcooled to −78° C. nBuLi (1.47 mL of 2.5M solution in hexanes, 3.7 mmole)was added dropwise and the reaction mixture was allowed to warm to roomtemperature over several hours. The reaction was quenched with saturatedammonium chloride solution and diluted with ethyl acetate andtransferred to a separatory funnel. The organic layer was washed withbrine and dried over sodium sulfate. Filtration and evaporation gave thecrude product, which was subjected to flash chromatography using agradient of 0 to 35% ethyl acetate/hexane, collecting all fractions andmonitoring by ELSD. Clean fractions combined and evaporated to give 732mg (56%) of the desired product as a colorless oil.

Step 2: Synthesis of benzyl4-(4-bromophenyl)-4-fluoropiperidine-1-carboxylate

Benzyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (731 mg, 1.87mmole) was dissolved in 8 mL dichloromethane and cooled to −78° C. DAST(272 uL, 2.06 mmole) was added dropwise and then allowed to warm slowlyto room temperature over a couple hours. The reaction was quenched withsaturated sodium bicarbonate solution and diluted with dichloromethaneand transferred to a separatory funnel. The organic layer was dried oversodium sulfate, filtered and evaporated to give the crude product.Purification by flash chromatography using a gradient of 0 to 35% ethylacetate/hexane, collecting all fractions and monitoring by ELSD. Cleanfractions combined and evaporated to give 236 mg (32%) of the desiredproduct as a colorless oil.

K. Synthesis of tert-butyl3-(6-chloropyridin-3-yl)-3-methylpiperazine-1-carboxylate Step 1:Synthesis of ethyl 2-(6-chloropyridin-3-yl)propanoate

A solution of lithium bis(trimethylsilyl)amide in THF (1 M, 14 mL, 14.0mmol) was added to a solution of ethyl 2-(6-chloropyridin-3-yl)acetate(2.5 g, 12.5 mmol) in THF at −78° C. under nitrogen. After stirred at−78° C. for 2 h, methyl iodide (1.94 g, 13.7 mmol) was added. Themixture was stirred at 20° C. for another 8 h. Worked up, concentratedand purified with silica gel column chromatography, eluting with 0%-10%EA/PE, to give the title compound (1.5 g, 83% purity in LCMS, yield 46%)as yellow oil. MS (ES+) C₁₀H₁₂ClNO₂ requires: 213, 215, found: 214, 216[M+H]⁺.

Step 2: Synthesis of ethyl 2-bromo-2-(6-chloropyridin-3-yl)propanoate

A solution of ethyl 2-(6-chloropyridin-3-yl)propanoate (1.5 g, 5.80mmol), N-bromosuccinimide (1.23 g, 6.95 mmol) and(E)-azobis(isobutyronitrile) (95 mg, 0.58 mmol) in perchloromethane (50mL) was stirred at 80° C. for 48 h under nitrogen. The mixture wascooled and concentrated in vacuo. The residue was purified with silicagel column chromatography, eluting with 0%˜10% EA/PE, to give the titlecompound (1.9 g, 75% purity in LCMS, yield 84%) as a yellow oil. MS(ES+) C₁₀H₁₁BrClNO₂ requires: 291, 293, found: 292, 294 [M+H]⁺.

Step 3: Synthesis of 3-(6-chloropyridin-3-yl)-3-methylpiperazin-2-one

A solution of ethyl 2-bromo-2-(6-chloropyridin-3-yl)propanoate (1.2 g,4.10 mmol) in ethane-1,2-diamine (5 mL) was stirred at 25° C. for 18 h.Diluted with DCM and washed with brine. Concentrated, the residue waspurified with silica gel column chromatography, eluting with 100% EA, togive the title compound (600 mg, yield 63%) as a yellow solid. MS (ES+)C₁₀H₁₂C1N₃O requires: 225, 227, found: 226, 228 [M+H]⁺.

Step 4: Synthesis of tert-butyl3-(6-chloropyridin-3-yl)-3-methylpiperazine-1-carboxylate

A solution of borane in tetrahydrofuran (22 mL, 1 M, 22.0 mmol) wasadded dropwise to a solution of3-(6-chloropyridin-3-yl)-3-methylpiperazin-2-one (500 mg, 2.21 mmol) intetrahydrofuran (10 mL), and then stirred at 80° C. for 18 h undernitrogen. Cooled, quenched with MeOH and refluxed with HCl/dioxanesolution. The mixture was basified with 1 M NaOH solution to pH=10-12,and then di-tert-butyl dicarbonate (1.23 g, 5.64 mmol) was added.Stirred at 20° C. for 18 h. Diluted with EA and washed with water.Concentrated, the residue was purified with silica gel columnchromatography, eluting with 0%-10% MeOH/EA, to give the title compound(200 mg, yield 34%) as a white solid. MS (ES+) C₁₅H₂₂ClN₃O₂ requires:311, 313, found: 312, 314 [M+H]⁺.

L. Synthesis of2-chloro-3-fluoro-5-(1-isopropyl-4-methoxypiperidin-4-yl)pyridine Step1: Synthesis of tert-butyl4-(6-chloro-5-fluoropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate

To a solution of 5-bromo-2-chloro-3-fluoropyridine (2 g, 9.50 mmol) inTHF (60 mL) at −78° C. was added nBuLi (4 mL, 2.4 M in hexane) dropwise.The solution was stirred at −78° C. for 2 h. Then a solution oftert-butyl 4-oxopiperidine-1-carboxylate (1.89 g, 9.50 mmol) in THF (10mL) was added dropwise. The resulting solution was stirred at −78° C.for 2 h. The reaction was quenched carefully by addition of water andextracted with EtOAc. The organic layer was washed with water and brine,concentrated and purified by silica gel column chromatography (petroleumether/ethyl acetate=10/1 to 2/1) to afford the title product (2 g, 64%)as a white solid. MS (ES+) C₁₅H₂₀ClFN₂O₃ requires: 330, found: 331[M+H]⁺.

Step 2: Synthesis of tert-butyl4-(6-chloro-5-fluoropyridin-3-yl)-4-methoxypiperidine-1-carboxylate

To a solution of tert-butyl4-(6-chloro-5-fluoropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (2g, 6.04 mmol) in dry DMF (20 mL) was added NaH (60%) (313 mg, 7.85 mmol)at 0° C. The mixture was stirred at 0° C. for 1 h. Then iodomethane(1.28 g, 9.06 mmol) was added. The mixture was stirred at RT overnight.After that, the mixture was slowly poured into ice water (200 mL) andstirred for 1 h. The solid was collected by filtration and dried toafford the title compound (1.5 g, 72%) as a white solid. MS (ES+)C₁₆H₂₂ClFN₂O₃ requires: 344, found: 345 [M+H]⁺.

Step 3: Synthesis of2-chloro-3-fluoro-5-(4-methoxypiperidin-4-yl)pyridine

To a solution of tert-butyl4-(6-chloro-5-fluoropyridin-3-yl)-4-methoxypiperidine-1-carboxylate (1.5g, 4.35 mmol) in dioxane (10 mL) was added HCl/dioxane (4 N, 10 mL). Themixture was stirred at RT for 12 h. After that, the solution wasconcentrated. The residue was used in the next step without furtherpurification. MS (ES+) C₁₁H₁₄ClFN₂O requires: 244, found: 245 [M+H]⁺.

Step 4: Synthesis of2-chloro-3-fluoro-5-(1-isopropyl-4-methoxypiperidin-4-yl)pyridine

A mixture of 2-chloro-3-fluoro-5-(4-methoxypiperidin-4-yl)pyridine (1 g,4.08 mmol), 2-iodopropane (693 mg, 4.08 mmol) and triethylamine (1.23 g,12.2 mmol) in CH₃CN (15 mL) was stirred at 80° C. overnight. After that,the solution was concentrated and purified by silica gel columnchromatography (DCM/MeOH=10/1) to afford the title compound (800 mg,68%) as a yellow solid. MS (ES+) C₁₄H₂₀ClFN₂O requires: 286, found: 287[M+H]⁺.

M. Synthesis of (R)-3-(4-bromophenyl)-1-isopropylpiperidine and(S)-3-(4-bromophenyl)-1-isopropylpiperidine Step 1: Chiral separation of3-(4-bromophenyl)piperidine hydrochloride

Racemic 3-(4-bromophenyl)piperidine hydrochloride was separated intosingle enantiomers using the following appropriately scaled chiral HPLCconditions: Column: CD-PH 250×4.6 mm I.D., 5 um Mobile phase:A:waterwith 0.1% TFA B:acetonitrile with 0.1% TFA A/B=70/30 Flow rate: 1.0mL/min Wavelength: 220 nm.

Step 2: Synthesis of (S)-3-(4-bromophenyl)-1-isopropylpiperidine

A mixture of (S)-3-(4-bromophenyl)piperidine hydrochloride (3.1 g, 11.2mmol), 2-bromopropane (2.75 g, 22.4 mmol) and K₂CO₃ (4.62 g, 33.5 mmol)in CH₃CN (20 mL) was stirred at 70° C. for 16 hrs. The mixture wasdiluted with EtOAc and washed with brine. The organic layer wasconcentrated in vacuo to afford the title compound (2.9 g, yield 91%) asa yellow oil. MS (ES+) C₁₄H₂₀BrN requires: 281, found: 282 [M+H]⁺.

N. Synthesis of5-(4-bromo-2-fluorophenyl)-1-isopropyl-1,2,3,6-tetrahydropyridine Step1: Synthesis of tert-butyl 3-(4-bromo-2-fluorophenyl)-5,6-dihydropyridine-1 (2H)-carboxylate

A mixture of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(4.3 g, 13.9 mmol), 4-bromo-2-fluoro-1-iodobenzene (6.25 g, 20.8 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.54 g,2.78 mmol) and potassium carbonate (5.75 g, 41.7 mmol) in dioxane/H₂O(L/10 mL) was degassed with Nitrogen for three times and then heated at70° C. for 3 h. The reaction mixture was cooled to room temperature andconcentrated to get crude product, which was purified by silica gelchromatography (petroleum ether/ethyl acetate=4/1) to afford the titlecompound (3.7 g, yield 75%) as a brown oil. MS (ES+) C₁₆H₁₉BrFNO₂requires: 355, found: 300 [M-56+H]⁺.

Step 2: Synthesis of5-(4-bromo-2-fluorophenyl)-1,2,3,6-tetrahydropyridine HCl salt

To a mixture of tert-butyl3-(4-bromo-2-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (3.7 g,10.3 mmol) in dioxane (20 ml) was added dioxane/HCl (4 M, 20 mL). Thereaction mixture was stirred at room temperature for 3 hours.Concentrated under reduced pressure to afford the title compound (2.6 g,yield 86%) as a brown solid, which was directly used into the next stepwithout further purification. MS (ES+) C₁₁H₁₁BrFN requires: 255, found:256 [M+H]⁺.

Step 3: Synthesis of5-(4-bromo-2-fluorophenyl)-1-isopropyl-1,2,3,6-tetrahydropyridine

To a solution of 5-(4-bromo-2-fluorophenyl)-1,2,3,6-tetrahydropyridineHCl salt (150 mg, 585 μmol) and potassium carbonate (241 mg, 1.75 mmol)in acetonitrile (10 ml) was added 2-iodopropane (496 mg, 2.92 mmol). Thesolution was stirred at 60° C. for 6 hours. Cooled to room temperatureand extracted with EtOAc after water was added. The organic phase waswashed with water and brine, dried over Na₂SO₄, and concentrated todryness to afford the title compound as a yellow solid which was usedwithout further purification (140 mg, crude). MS (ES+) C₁₄H₁₇BrFNrequires: 297, found: 298 [M+H]⁺.

O. Synthesis of 3-(4-bromophenyl)-1-isopropyl-3-methylpiperazine Step 1:Synthesis of methyl 2-(4-bromophenyl)acetate

A mixture of 2-(4-bromophenyl)acetic acid (10 g, 46.5 mmol) in MeOH (100mL, with 2 mL of conc. H₂SO₄) was refluxed for 4 h. The mixture wasconcentrated and diluted with EtOAc. The organic was washed with waterand brine, dried and concentrated to give the title product (10.6 g,yield 100%). MS (ES+) C₉H₉BrO₂ requires: 229 found 230 [M+H]⁺.

Step 2: Synthesis of methyl 2-(4-bromophenyl)propanoate

To a solution of methyl 2-(4-bromophenyl)acetate (1 g, 4.36 mmol) in dryTHF (20 mL) was added LiHMDS (5.23 mL, 1 M) dropwise at −78° C. underN₂. The mixture was stirred at 0° C. for 2 h. After MeI (1.23 g, 8.72mmol) was added at −78° C., the mixture was stirred at 20° C. for 16 h.Quenched with NH₄Cl sat. and extracted with EtOAc. The organic wasconcentrated and purified by silica gel column (PE/EtOAc=I/O to 100/1)to give the title product (642 mg, yield 61%). MS (ES+) C₁₀H₁₁BrO₂requires: 243, found 244 [M+H]⁺.

Step 3: Synthesis of methyl 2-bromo-2-(4-bromophenyl)propanoate

A mixture of methyl 2-(4-bromophenyl)propanoate (30 g, 123 mmol), AIBN(2.01 g, 12.3 mmol) and NBS (32.9 g, 184 mmol) in CCl₄ (300 mL) wasrefluxed for 16 h. Cooled to RT and filtered. After concentrated, theresidue was used into the next step without further purification.

Step 4: Synthesis of 3-(4-bromophenyl)-3-methylpiperazin-2-one

To a solution of methyl 2-bromo-2-(4-bromophenyl)propanoate (39 g, 121mmol) in EtOH (200 mL) was added ethane-1,2-diamine (14.5 g, 242 mmol).The mixture was stirred at RT for 16 h. Filtered off solid, concentratedand purified by silica gel column (EtOAc) to give the title product (12g, yield 37%). MS (ES+) C₁₁H₁₃BrN₂O requires: 269, found 270 [M+H]⁺.

Step 5: Synthesis of tert-butyl3-(4-bromophenyl)-3-methylpiperazine-1-carboxylate

A solution of 3-(4-bromophenyl)-3-methylpiperazin-2-one (12 g, 44.5mmol) and BH₃ (250 mL, 1 M in THF) was stirred at 80° C. overnight.Cooled to RT and quenched with MeOH. After concentrated, the residue wasdissolved in MeOH (100 mL), followed by addition of HCl (250 mL, aq, 1M). The mixture was stirred at 80° C. for 30 min. Cooled to RT. NaOH (12g, 0.3 mol) was added, followed by addition of Boc₂O (11.6 g, 53.3mmol). The mixture was stirred at RT overnight. Extracted with EtOAc.The organic was concentrated and purified by silica gel column DCM/MeOH(50/1) to give the title product (10 g, yield 63%). MS (ES+)C₁₆H₂₃BrN₂O₂ requires: 355, found 356 [M+H]⁺.

The racemic product (10 g) was separated by chiral-HPLC to give twosingle enantiomers: P1 (4.63 g) and P2 (4.46 g). Chiral conditions:Co-Solvent: MeOH(0.2% Methanol Ammonia); Column: OZ—H 100*4.6 mm 5 um;Column Temperature: 39.9.

Step 6: Synthesis of 2-(4-bromophenyl)-2-methylpiperazine

To a mixture of tert-butyl3-(4-bromophenyl)-3-methylpiperazine-1-carboxylate (1.8 g, 5.06 mmol) inDCM/MeOH (10 mL/10 mL) was added HCl/dioxane (14 mL, 4 M). The mixturewas stirred at RT for 1 h, concentrated, and the residue was dissolvedin NH₃.MeOH (8 mL, 7 mL). DCM (20 mL) was added. Filtered off solid andthen concentrated to give the title product (1.2 g, yield 98%). MS (ES+)C₁₆H₂₃BrN₂O₂ requires: 255, found 256 [M+H]⁺.

Step 7: Synthesis of 3-(4-bromophenyl)-1-isopropyl-3-methylpiperazine

A mixture of 2-(4-bromophenyl)-2-methylpiperazine (1.3 g, 5.09 mmol),2-iodopropane (994 mg, 5.85 mmol) and DIPEA (3.28 g, 25.4 mmol) in THF(50 mL) was stirred at 60° C. for 16 h. Concentrated and purified bysilica gel column (EtOAc) to give the title product (1.3 g, yield 86%).MS (ES+) C₁₄H₂₁BrN₂ requires: 297, found 298 [M+H]⁺.

P. Synthesis of 6′-bromo-1-isopropyl-1,2,5,6-tetrahydro-3,3′-bipyridineStep 1: Synthesis of tert-butyl 6′-bromo-5, 6-dihydro-[3,3′-bipyridine]-1 (2H)-carboxylate

A mixture of 2-bromo-5-iodopyridine (3.66 g, 12.9 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(4 g, 12.9 mmol), Pd(dppf)Cl₂ (944 mg, 1.29 mmol) and K₂CO₃ (2.66 g,19.3 mmol) in dioxane/water (10/1, 20 mL) was irradiated under microwaveat 120° C. for 2 h. Concentrated and purified by silica gel columnPE/EtOAc (10/1) to give title product (2.12 g, yield 48%). MS (ES+)C₁₅H₁₉BrN₂O₂ requires: 339 found 340 [M+H]⁺.

Step 2: Synthesis of 6′-bromo-1,2,5,6-tetrahydro-3,3′-bipyridine

To a solution of tert-butyl 6′-bromo-5,6-dihydro-[3,3′-bipyridine]-1(2H)-carboxylate (2.12 g, 6.24 mmol) in DCM (20 mL) was added TFA (4 mL)at RT, and then stirred for 1 h. The mixture was diluted with water,adjusted pH to 7-8 with NaHCO₃ sat., and extracted with DCM. Dried andconcentrated to give the title product (1.49 g, yield 100%). MS (ES+)C₁₀H₁₁BrN₂ requires: 239, found 240 [M+H]⁺.

Step 3: Synthesis of6′-bromo-1-isopropyl-1,2,5,6-tetrahydro-3,3′-bipyridine

A mixture of 6′-bromo-1,2,5,6-tetrahydro-3,3′-bipyridine (1.49 g, 6.23mmol), DIPEA (2.39 g, 18.6 mmol) and 2-iodopropane (3.16 g, 18.6 mmol)in MeCN (50 mL) was stirred at 60° C. for 16 h. Concentrated andpurified by silica gel column DCM/MeOH (20/1) to give title product(1.75 g, yield 100%). MS (ES+) C₁₃H₁₇BrN₂ requires: 281 found 282[M+H]⁺.

Q. Synthesis of 2-bromo-5-(4-ethoxy-1-isopropylpiperidin-4-yl)pyridineStep 1: Synthesis of tert-butyl4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate

To a solution of 2-bromo-5-iodopyridine (18.5 g, 65.2 mmol) in 150 mL ofTHF was added n-BuLi (26 mL, 2.5 M in hexane) dropwise under N₂ at −78°C. The resulting solution was stirred at −78° C. for 2 h. A solution oftert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.2 mmol) in 30 mL ofTHF was added dropwise. The mixture was stirred at −78° C. for another 1h. The reaction was quenched by addition of sat. NH₄Cl solution andextracted with EtOAc. The organic phase was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography toafford the title product (12.6 g, 70% yield) as a white solid.

Step 2: Synthesis of tert-butyl4-(6-bromopyridin-3-yl)-4-ethoxypiperidine-1-carboxylate

To a solution of tert-butyl4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (2.5 g, 6.99mmol) in 100 mL of THF was added NaH (60%, 415 mg, 10.4 mmol) at 0° C.The mixture was stirred at 0° C. for 30 min. Then bromoethane (1.13 g,10.4 mmol) was added. The resulting mixture was stirred at rt for 4 h.The reaction was quenched by addition of water carefully and extractedwith EtOAc. The organic phase was washed with brine and water, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel chromatography to afford the title compound (2.4 g, 89%yield) as a white solid.

Step 3: Synthesis of 2-bromo-5-(4-ethoxypiperidin-4-yl)pyridine

To a solution of tert-butyl4-(6-bromopyridin-3-yl)-4-ethoxypiperidine-1-carboxylate (2.4 g, 6.22mmol) in dioxane (80 mL) was added HCl/dioxane (15 mL, 4.0 M) at 25° C.,and the resulting mixture was stirred at 25° C. for 2 h. LC-MS showedthat the reaction was completed. Evaporated to dryness to afford thetitle compound (1.5 g) as HCl salt, which was used for the next stepwithout further purification.

Step 4: Synthesis of2-bromo-5-(4-ethoxy-1-isopropylpiperidin-4-yl)pyridine

A mixture of 2-bromo-5-(4-ethoxypiperidin-4-yl)pyridine (1.5 g, 5.25mmol) and potassium carbonate (2.18 g, 15.7 mmol) in MeCN (100 mL) wasadded iodomethane (2.66 g, 15.7 mmol) and then stirred at 60° C. for 5h. Concentrated, the residue was diluted with DCM/water (200 mL/200 mL)and extracted with DCM. The combined organic layers were dried overNa₂SO₄ and concentrated to give the title product (1.4 g), which wasused for the next step without further purification.

R. Synthesis of2-bromo-5-(1-(1-(difluoromethoxy)propan-2-yl)-4-methoxypiperidin-4-yl)pyridineStep 1: Synthesis of2-(4-(6-bromopyridin-3-yl)-4-methoxypiperidin-1-yl)propan-1-ol

To a solution of 2-bromo-5-(4-methoxypiperidin-4-yl)pyridine (10 g, 36.8mmol) and 1-hydroxypropan-2-one (54.5 g, 736 mmol) in DCM (100 mL) andCH₃OH (100 mL) was added HOAc (1.0 mL) at 0° C., and then sodiumcyanoborohydride (11.5 g, 184 mmol) was added. The mixture was stirredat 35° C. for 16 h. After that, the mixture was quenched by addition ofNaHCO₃ solution and extracted with DCM. The organic layers wereconcentrated and purified by silica gel column (DCM/CH₃OH=10/1) to getthe title compound (8.0 g, yield 66%) as a colorless oil. MS (ES+)C₁₄H₂₁BrN₂O₂ requires: 328, 330, found 329, 331 [M+H]⁺.

Step 2: Chiral separation of2-(4-(6-bromopyridin-3-yl)-4-methoxypiperidin-1-yl)propan-1-ol

The two enantiomers were separated on an AY-H column (250*4.6 mm, 5 um;Mobile Phase: n-Hexane (0.1% DEA):EtOH(0.1% DEA)=70:30; Temperature: 40°C.; Flow: 1.0 mL/min) and the fractions were measured at wavelengths 214nm and 254 nm on a SHIMADZU Instrument.

Step 3: Synthesis of2-bromo-5-(1-(1-(difluoromethoxy)propan-2-yl)-4-methoxypiperidin-4-yl)pyridine

To a mixture of2-(4-(6-bromopyridin-3-yl)-4-methoxypiperidin-1-yl)propan-1-ol (100 mg,303 μmol) and CuI (86 mg, 0.45 mmol) in 4 mL of CH₃CN was added asolution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (268 mg, 1.51mmol) dropwise in 2 mL of CH₃CN at 45° C. under N₂. The resultingmixture was stirred at 45° C. for 2 hrs. The solvent was removed invacuo and the residue was purified by silica gel column(EtOAc/CH₃OH=20/1) to afford the title product (40 mg, yield 35%) as ayellow oil. MS (ES+) C₁₅H₂₁BrF₂N₂O₂ requires: 378, 380, found 379, 381[M+H]⁺.

S. Synthesis of2-bromo-5-(4-methoxy-1-(1-methoxypropan-2-yl)piperidin-4-yl)pyrine Step1: Synthesis of(S)-2-bromo-5-(4-methoxy-1-(1-methoxypropan-2-yl)piperidin-4-yl)pyridine

A mixture of 2-bromo-5-(4-methoxypiperidin-4-yl)pyridine (800 mg, 2.95mmol), (R)-1-methoxypropan-2-yl methanesulfonate (992 mg, 5.90 mmol) andK₂CO₃ (1.22 g, 8.85 mmol) in CH₃CN (30 mL) was heated to 70° C. for 72h. Concentrated and passed a column (silica gel, DCM:MeOH=20:1) to givethe title product (0.5 g, 50%) as a yellow oil. MS (ES+) C₁₅H₂₃BrN₂O₂requires: 342, found 343 [M+H]⁺.

Step 2: Synthesis of(R)-2-bromo-5-(4-methoxy-1-(1-methoxypropan-2-yl)piperidin-4-yl)pyridine

A mixture of 2-bromo-5-(4-methoxypiperidin-4-yl)pyridine hydrochloride(200 mg, 0.65 mmol), (S)-1-methoxypropan-2-yl methanesulfonate (218 mg,1.30 mmol) and K₂CO₃ (269 mg, 1.95 mmol) in CH₃CN (5 mL) was heated to70° C. for 72 h. Concentrated and passed a column (silica gel,DCM:MeOH=20:1) to give the title product (100 mg, 45%) as a yellow oil.MS (ES+) C₁₅H₂₃BrN₂O₂ requires: 342, found 343 [M+H]⁺.

T. Synthesis of (3S,4S)-3-(4-bromophenyl)-1-isopropylpiperidin-4-ol Step1: Synthesis of tert-butyl 3-(4-bromophenyl)-5, 6-dihydropyridine-1(2H)-carboxylate

A mixture of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(10 g, 32.3 mmol), 1-bromo-4-iodobenzene (9.13 g, 32.3 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.35 g,3.22 mmol) and sodium carbonate (10.2 g, 96.8 mmol) in dioxane (80 mL)and water (20 mL) was purged with N₂ and stirred at 75° C. for 2 h.After that, the solution was cooled to RT and purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate=10/1 to 5/1) toafford the title compound (8 g, 73%) as a colorless oil. MS (ES+)C₁₆H₂₀BrNO₂ requires: 337, 339, found: 282, 284 [M-55]⁺.

Step 2: Synthesis of (3r,4r)-tert-butyl3-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

To a cooled solution of borane-methyl sulfide complex (26.5 mL, 26.5mmol) in anhydrous tetrahydrofuran (80 mL) under an atmosphere ofnitrogen was added a solution of tert-butyl3-(4-bromophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (7.5 g, 22.1mmol) in tetrahydrofuran (20 mL). The resulting mixture was stirred atroom temperature for 17 hours, then cooled in an ice bath, and sodiumhydroxide (12.65 mL of a 2 N solution, 24.25 mmol) added in a dropwisemanner, followed by hydrogen peroxide (9.2 mL of a 30% solution). Theresulting mixture was stirred at RT for 3˜5 hours, then poured intowater (100 mL) and extracted with ethyl acetate (3×150 mL). The combinedorganic layers were washed with water (150 mL), saturated NaHCO₃ (150mL) and saturated NaCl (150 mL), dried over Na₂SO₄, filtered,concentrated and purified by silica gel column chromatography (petroleumether/ethyl acetate=5/1 to 1/1) to afford the title compound (trans-,3.5 g, 44%) as a white solid. MS (ES+) C₁₆H₂₀BrNO₂ requires: 355, 357,found: 300, 302 [M-55]⁺.

Step 3: Separation of (3S,4S)-tert-butyl3-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate and(3R,4R)-tert-butyl 3-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

The enantiomers were separated on a S,S-Whelk-O1 column (4.6*100*5 um;Co-Solvent: MeOH (0.2% Methanol Ammonia); Column Temperature: 40° C.;CO₂ Flow Rate:3.6.

Step 4: Synthesis of (3S,4S)-3-(4-bromophenyl)piperidin-4-ol

To a solution of (3S,4S)-tert-butyl3-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (1.3 g, 3.64 mmol)in dioxane (20 mL) was added HCl/dioxane (4 mol/L, 10 mL). The mixturewas stirred at RT for 12 h. After that, the solution was concentrated,and the residue was used in the next step without further purification.MS (ES+) C₁₁H₁₄BrNO requires: 255, 257, found: 256, 258 [M+H]⁺.

Step 5: Synthesis of (3S,4S)-3-(4-bromophenyl)-1-isopropylpiperidin-4-ol

A mixture of (3S,4S)-3-(4-bromophenyl)piperidin-4-ol (900 mg, 3.51mmol), 2-iodopropane (1.19 g, 7.02 mmol) and triethylamine (1.06 g, 10.5mmol) in CH₃CN (30 mL) was stirred at 70° C. overnight. After that, thesolution was concentrated and purified by silica gel columnchromatography (petroleum ether/ethyl acetate/NH₃.MeOH=10/10/1) toafford the title compound (900 mg, 87%) as a white solid. MS (ES+)C₁₄H₂₀BrNO requires: 297, 299, found: 298, 300 [M+H]⁺.

U. Synthesis of4-(4-bromophenyl)-4-methoxy-1-(1-methoxypropan-2-yl)piperidine Step 1:Synthesis of tert-butyl4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

To a solution of 1,4-dibromobenzene (25.9 g, 110 mmol) in dry THF (250mL) was added n-BuLi (2.5 M, 48.0 mL, 120.0 mmol) dropwise at −78° C.The mixture was stirred at −78° C. for 1 h before tert-butyl4-oxopiperidine-1-carboxylate (20 g, 100 mmol) in dry THF (100 mL) wasadded dropwise at −78° C. The reaction mixture was stirred at −78° C.for another 1 h and warmed to RT slowly. LC-MS showed the reaction wascompleted. The reaction mixture was quenched with saturated NH₄Cl andextracted with EA (200 mL×3). The organic layer was washed with waterand brine, dried over Na₂SO₄, filtrated, concentrated and purified bysilica gel chromatograph (PE:EA=5:1) to give the title product (22 g,yield: 62%) as a white solid. MS (ES+) C₁₆H₂₂BrNO₃ requires: 355, 357found 356, 358 [M+H]⁺.

Step 2: Synthesis of tert-butyl4-(4-bromophenyl)-4-methoxypiperidine-1-carboxylate

Sodium hydride (60%, 782 mg, 32.6 mmol) was added to a solution oftert-butyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (7.8 g,21.8 mmol) in DMF. This mixture was stirred at 20° C. for 30 min undernitrogen. Iodomethane (32.6 mmol, 4.62 g) was then added.

Stirred at 20° C. for 2 h. Dissolved in water and extracted with EA. EAphase was dried and purified by silica gel chromatograph, eluting with1/4 EA/PE to give the title product as a yellow oil (8.0 g, ˜80% inLCMS, yield 79%). MS (ES+) C₁₇H₂₄BrNO₃ requires: 369, 371, found: 282,284 [M+H]⁺.

Step 3: Synthesis of 4-(4-bromophenyl)-4-methoxypiperidine HCl salt

A solution of 4 M HCl in dioxane (25 mL, 100.0 mmol) was added to astirred solution of tert-butyl4-(4-bromophenyl)-4-methoxypiperidine-1-carboxylate (3.7 g, 10.0 mmol)in MeOH (20 mL) at 25° C., and stirred for 3 h under N₂. Afterconcentrated, the crude product (2.5 g, yield 89%, yellow solid) wasused into the next reaction directly without further purification. MS(ES+) C₁₂H₁₆BrNO requires: 269, 271, found: 270, 272 [M+H]⁺.

Step 4a: Synthesis of (R)-1-methoxypropan-2-yl methanesulfonate

To a mixture of (R)-1-methoxypropan-2-ol (2.0 g, 22.1 mmol) andtriethylamine (6.70 g, 66.3 mmol) in DCM (10 mL) was addedmethanesulfonyl chloride (3.79 g, 33.1 mmol) dropwise at 0° C. Themixture was stirred at rt for 16 hrs. The mixture was quenched with sat.NaHCO₃ solution, diluted with DCM, washed with water and dried overNa₂SO₄ anhydrous. The organic layer was concentrated in vacuo to affordthe title compound (3.0 g, yield 80%) as a yellow oil MS (ES+) C₅H₁₂O₄Srequires: 168, found: 169 [M+H]⁺.

Step 4b: Synthesis of (S)-1-methoxypropan-2-yl methanesulfonate

To a mixture of (S)-1-methoxypropan-2-ol (1.5 g, 16.6 mmol) andtriethylamine (5.03 g, 49.8 mmol) was added methanesulfonyl chloride(1.92 mL, 24.9 mmol) at 0° C. The mixture was stirred at rt for 16 hrs.The mixture was diluted with DCM, washed with sat. NaHCO₃ solution anddried over Na₂SO₄ anhydrous. The organic layer was concentrated in vacuoto afford the title compound (2.3 g, yield 82%) as a yellow oil MS (ES+)C₅H₁₂O₄S requires: 168, found: 169 [M+H]⁺.

Step 5a: Synthesis of(S)-4-(4-bromophenyl)-4-methoxy-1-(1-methoxypropan-2-yl)piperidine

A solution of 4-(4-bromophenyl)-4-methoxypiperidine (250 mg, 0.93 mmol),potassium carbonate (127 mg, 0.93 mmol), potassium iodide (153 mg, 0.93mmol) and (R)-1-methoxypropan-2-yl methanesulfonate (186 mg, 1.11 mmol)in DMF (5 mL) was stirred at 60° C. for 5 h under N₂. Dissolved in EA,and washed with water and brine. After dried and concentrated, theresidue was purified by silica gel chromatograph, eluting with 1/10MeOH/EA to. give desired product (100 mg, 65% purity in LCMS, yield 21%)as a brown paste. MS (ES+) C₁₆H₂₄BrNO₂ requires: 341, found: 342, 344[M+H]⁺.

Step 5b: Synthesis of(R)-4-(4-bromophenyl)-4-methoxy-1-(1-methoxypropan-2-yl)piperidine

A solution of 4-(4-bromophenyl)-4-methoxypiperidine (250 mg, 0.93 mmol),potassium carbonate (127 mg, 0.93 mmol), potassium iodide (153 mg, 0.93mmol) and (S)-1-methoxypropan-2-yl methanesulfonate (155 mg, 0.93 mmol)in DMF (5 mL) was stirred at 60° C. for 5 h under N₂. Dissolved in EA,and washed with water and brine. After dried and concentrated, theresidue was purified by silica gel chromatograph, eluting with 1/10MeOH/EA, to give the title compound (106 mg, 85% purity in LCMS, yield34%) as a yellow paste. MS (ES+) C₁₆H₂₄BrNO₂requires: 341, 343, found:342, 344 [M+H]⁺.

V. Synthesis of (S)-5-(1-isopropylpiperidin-3-yl)pyridin-2-yltrifluoromethanesulfonate Step 1: Synthesis of tert-butyl3-(6-(benzyloxy)pyridin-3-yl)-5, 6-dihydropyridine-1 (2H)-carboxylate

A mixture of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(5 g, 16.1 mmol), 2-(benzyloxy)-5-bromopyridine (6.36 g, 24.1 mmol),Pd(dppf)Cl₂ (818 mg, 1.12 mmol) and K₂CO₃ (4.44 g, 32.2 mmol) indioxane/water (40 mL/5 mL) was purged with N₂ for three times andstirred at 100° C. for 16 hrs. The mixture was concentrated and purifiedby flash column chromatography (PE/EtOAc=10:1) to afford the titlecompound (5.0 g, yield 84%) as a yellow oil. MS (ES+) C₂₂H₂₆N₂O₃requires: 366, found: 367 [M+H]⁺.

Step 2: Synthesis of (S)-tert-butyl3-(6-hydroxypyridin-3-yl)piperidine-1-carboxylate (P1) and(R)-tert-butyl 3-(6-hydroxypyridin-3-yl)piperidine-1-carboxylate (P2)

A mixture of tert-butyl6′-(benzyloxy)-5,6-dihydro-[3,3′-bipyridine]-1(2H)-carboxylate (2.5 g,6.82 mmol) and Pd/C (1.44 g) in EtOAc (10 mL) was stirred at RT for 16hrs under H₂ (H₂ balloon). The mixture was filtered through a pad ofCelite and purified by Prep-HPLC to afford racemic compound (1.1 g) as awhite solid, which was separated by chiral HPLC (Chiral condition:Co-Solvent: MeOH(0.2% Methanol Ammonia); Column: OZ—H 100*4.6 mm 5 um;Column Temperature: 36.8; C02 Flow Rate:3; Co-Solvent Flow Rate:1) toafford the title compound P1 (500 mg, yield 26%) as a white solid. MS(ES+) C₁₅H₂₂N₂O₃ requires: 278, found: 279 [M+H]⁺ and P2 (500 mg, yield26%) as a white solid. MS (ES+) C₁₅H₂₂N₂O₃ requires: 278, found: 279[M+H]⁺.

Step 3: Synthesis of (S)-tert-butyl3-(6-(trifluoromethylsulfonyloxy)pyridin-3-yl)piperidine-1-carboxylate

To a mixture of (S)-tert-butyl3-(6-hydroxypyridin-3-yl)piperidine-1-carboxylate (500 mg, 1.79 mmol)and pyridine (431 μL, 5.37 mmol) in DCM (5 mL) was addedtrifluoromethanesulfonic anhydride (450 μL, 2.68 mmol) dropwise at 0° C.The mixture was stirred at 0° C. for 30 min, diluted with DCM, washedwith ice water and dried over Na₂SO₄ anhydrous. The organic layer wasconcentrated in vacuo to afford the title compound (700 mg, yield 95%)as a yellow oil. MS (ES+) C₁₆H₂₁F₃N₂O₅S requires: 410, found: 411[M+H]⁺.

Step 4: Synthesis of (S)-5-(piperidin-3-yl)pyridin-2-yltrifluoromethanesulfonate hydrochloride

To a mixture of (S)-tert-butyl3-(6-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)piperidine-1-carboxylate(400 mg, 974 μmol) in DCM (2 mL) was added HCl in dioxane (1.21 mL, 4.84mmol). The mixture was stirred at RT for 4 hrs. The mixture wasconcentrated in vacuo to afford the title compound (330 mg, crude) as ayellow solid. MS (ES+) C₁₁H₁₄ClF₃N₂O₃S requires: 310, found: 311 [M+H]⁺.

Step 5: Synthesis of (S)-5-(1-isopropylpiperidin-3-yl)pyridin-2-yltrifluoromethanesulfonate

A mixture of (S)-5-(piperidin-3-yl)pyridin-2-yltrifluoromethanesulfonate hydrochloride (330 mg, 951 μmol),2-iodopropane (322 mg, 1.90 mmol) and triethylamine (288 mg, 2.85 mmol)in ACN (5 mL) was stirred at 60° C. for 16 hrs. The mixture wasconcentrated and purified by flash column chromatography (DCM/MeOH=10:1)to afford the title compound (250 mg, yield 74%) as a yellow oil MS(ES+) C₁₄H₁₉F₃N₂O₃S requires: 352, found: 353 [M+H]+.

W. Synthesis of4-(4-bromo-3-chlorophenyl)-1-isopropyl-1,2,3,6-tetrahydropyridine Step1: Synthesis of tert-butyl 4-(4-bromo-3-chlorophenyl)-5,6-dihydropyridine-1 (2H)-carboxylate

To a solution of 1-bromo-2-chloro-4-iodobenzene (4.9, 15.4 mmol) andtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(4.3 g, 13.9 mmol) in dioxane/H₂O (50 mL/20 mL) was added Pd(dppf)Cl₂(626 mg, 0.77 mmol) and K₂CO₃ (6.4 g, 46.2 mmol) at room temperatureunder nitrogen. The resulting mixture was stirred at 70° C. for 2 hours.Cooled to room temperature and extracted with EtOAc after additionalwater was added. The organic was washed with brine, dried over Na₂SO₄and concentrated to dryness to afford the crude product which waspurified by flash chromatography on silica gel eluting with PE/EA (10:1)to afford the title product (3.6 g, yield 70%) as a yellow solid. MS(ES+) C₁₆H₁₉BrClNO₂ requires: 371, found 372 [M+H]⁺.

Step 2: Synthesis of4-(4-bromo-3-chlorophenyl)-1,2,3,6-tetrahydropyridine TFA salt

To a solution of tert-butyl4-(4-bromo-3-chlorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (3.6 g,9.7 mmol) in DCM (20 mL) was added TFA (5 mL) dropwise at roomtemperature. The resulting mixture was stirred at room temperature for 3hours; LC-MS showed that the reaction was completed. The solution wasevaporated to dryness to afford the crude product which was used for thenext step without further purification (3.4 g, TFA salt). MS (ES+)C₁₁H₁₁BrClN requires: 271, found 272 [M+H]⁺.

Step 3: Synthesis of4-(4-bromo-3-chlorophenyl)-1-isopropyl-1,2,3,6-tetrahydropyridine

To a solution of 4-(4-bromo-3-chlorophenyl)-1,2,3,6-tetrahydropyridineTFA salt (3.4 g, 9.2 mmol) in acetonitrile (15 mL) was added TEA (2.8 g,27.6 mmol), followed by addition of isopropyl iodide (4.7 g, 27.6 mmol).The solution was heated at 70° C. for 6 hours; LC-MS showed that thereaction was completed. The crude product was purified by flashchromatography on silica gel eluting with PE/EA (1:1 to 1:3) to give thetitle product (2.4 g, yield 83%) as viscous oil. MS (ES+) C₁₄H₁₇BrClNrequires: 313, found 314 [M+H]⁺.

X. Synthesis of4-(4-bromo-3-fluorophenyl)-1-isopropyl-4-methoxypiperidine Step 1:Synthesis of tert-butyl4-(4-bromo-3-fluorophenyl)-4-hydroxypiperidine-1-carboxylate

To a solution of 1-bromo-2-fluoro-4-iodobenzene (15.0 g, 50.1 mmol) inTHF (150 mL) at −78° C. was added n-BuLi (20 mL, 2.4 M in hexane)dropwise. The solution was stirred at −78° C. for 2 h. Then, a solutionof tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.1 mmol) in THF (20mL) was added dropwise. After that, the resulting solution was stirredat −78° C. for 2 h. The reaction was quenched carefully by addition ofwater and extracted with EtOAc. The organic layer was washed with waterand brine, concentrated and purified by silica gel column chromatography(petroleum ether/ethyl acetate=10/1 to 2/1) to afford the title product(3 g, 16%) as a white solid. MS (ES+) C₁₆H₂₁BrFNO₃ requires: 373, 375,found: 300, 302 [M-73]⁺.

Step 2: Synthesis of (tert-butyl4-(4-bromo-3-fluorophenyl)-4-methoxypiperidine-1-carboxylate

To a solution of tert-butyl4-(4-bromo-3-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (3 g, 8.01mmol) in dry DMF (50 mL) was added NaH (60%) (416 mg, 10.4 mmol) at 0°C. The mixture was stirred at 0° C. for 1 h. Then, iodomethane (1.7 g,12.0 mmol) was added. The mixture was stirred at RT overnight. Afterthat, the mixture was slowly poured into ice water (200 mL) and stirredfor 1 h. The solid was collected via filtration and purified by silicagel column chromatography (petroleum ether/ethyl acetate=10/1 to 4/1) toafford the title compound (2.5 g, 80%) as a white solid. MS (ES+)C₁₇H₂₃BrFNO₃ requires: 387, 389, found: 300, 302 [M-87]⁺.

Step 3: Synthesis of 4-(4-bromo-3-fluorophenyl)-4-methoxypiperidine

To a solution of tert-butyl4-(4-bromo-3-fluorophenyl)-4-methoxypiperidine-1-carboxylate (2.5 g,6.43 mmol) in dioxane (20 mL) was added HCl/dioxane (4 N, 20 mL). Themixture was stirred at RT for 12 h. After that, the solution wasconcentrated and used in next step without further purification. MS(ES+) C₁₂H₁₅BrFNO requires: 287, 289, found: 288, 290 [M+H]⁺.

Step 4: Synthesis of4-(4-bromo-3-fluorophenyl)-1-isopropyl-4-methoxypiperidine

A mixture of 4-(4-bromo-3-fluorophenyl)-4-methoxypiperidine (1.6 g, 5.55mmol), 2-iodopropane (1.88 g, 11.1 mmol) and triethylamine (1.67 g, 16.6mmol) in CH₃CN (30 mL) was stirred at 80° C. overnight. After that, thesolution was concentrated and purified by silica gel columnchromatography (DCM/MeOH=10/1) to afford the title compound (1.5 g, 82%)as a yellow solid. MS (ES+) C₁₅H₂₁BrFNO requires: 329, 331, found: 330,332 [M+H]⁺.

Y. Synthesis of tert-butyl4-methyl-4-(4-(trifluoromethylsulfonyloxy)phenyl)piperidine-1-carboxylateStep 1: Synthesis of tert-butyl 4-(4-methoxyphenyl)-5,6-dihydropyridine-1 (2H)-carboxylate

To a solution of 1-bromo-4-methoxybenzene (6.0 g, 32.0 mmol) andtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(10.0 g, 32.0 mmol) in dioxane/H₂O (60 mL/30 mL) was added Pd(t-Bu₃P)₂(163 mg, 0.32 mmol) and Na₂CO₃ (6.8 g, 64 mmol) at room temperatureunder nitrogen. The resulting mixture was stirred at 70° C. for 2 hours.LC-MS showed that the reaction was completed. Cooled to room temperatureand extracted with EtOAc after additional water was added. The organicwas washed with brine, dried over Na₂SO₄ and concentrated to dryness toafford the crude product which was purified by flash chromatography onsilica gel eluting with PE/EA (10:1) to afford the title product (9.3 g,yield 97%) as a white solid. MS (ES+) C₁₇H₂₃NO₃ requires: 289, found 234[M+H-56]⁺.

Step 2: Synthesis of tert-butyl4-(4-methoxyphenyl)-4-methyl-3,4-dihydropyridine-1 (2H)-carboxylate

To a solution of tert-butyl4-(4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9.3 g, 32.0mmol) in THF (50 mL) was added n-BuLi (25.6 mL, 2.5 M in hexane) at −15°C. under nitrogen. The blood-red solution formed as the end of dropwiseaddition of n-BuLi. The reaction mixture was stirred at this temperaturefor 15 minutes. Me₂SO₄ (8.1 g, 64.0 mmol) was added dropwise to theabove solution at −15° C. The resulting mixture was stirred at roomtemperature for 30 minutes. NH₄OH (40 mL, 2.0 M) was added and theresulting mixture was extracted with EtOAc after water was added. Thecombined organics were washed with water and brine, dried over Na₂SO₄,and concentrated to dryness to afford the crude product which waspurified by flash chromatography on silica gel eluting with PE/EA (5:1)to give the title product (1.5 g, yield 15%) MS (ES+) C₁₈H₂₅NO₃requires: 303, found 248 [M+H-56]⁺.

Step 3: Synthesis of 4-(4-methyl-1,2,3,4-tetrahydropyridin-4-yl)phenol

To a solution of tert-butyl4-(4-methoxyphenyl)-4-methyl-3,4-dihydropyridine-1 (2H)-carboxylate (750mg, 2.5 mmol) in anhydrous DCM (15 mL) was added BBr₃ (2 mL, 17% in DCM)at 0° C. The resulting mixture was stirred at 0° C. for 6 hours; LC-MSshowed that reaction was completed. The reaction mixture was used forthe next step without work-up and purification.

Step 4: Synthesis of tert-butyl4-(4-(tert-butoxycarbonyloxy)phenyl)-4-methyl-3,4-dihydropyridine-1(2H)-carboxylate

To a solution of 4-(4-methyl-1,2,3,4-tetrahydropyridin-4-yl)phenol fromlast step was added TEA (7 mL) at 0° C. to adjust pH value to 9.0. Boc₂O(1.6 g, 7.5 mmol) and catalytic DMAP (30 mg, 0.25 mmol) was added. Theresulting mixture was stirred at room temperature for 16 hours; LC-MSshowed that the reaction was completed. Water was added and extractedwith EtOAc (×2). The combined organics were washed with brine, driedover Na₂SO₄, and concentrated to dryness to afford the crude productwhich was purified by flash chromatography on silica gel eluting withPE/EA (20:1 to 10:1) to afford the title product (470 mg, yield 51%) MS(ES+) C₂₂H₃₁NO₅ requires: 389, found 390 [M+H]⁺.

Step 5: Synthesis of tert-butyl4-(4-(tert-butoxycarbonyloxy)phenyl)-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl4-(4-(tert-butoxycarbonyloxy)phenyl)-4-methyl-3,4-dihydropyridine-1(2H)-carboxylate(470 mg, 1.2 mmol) in MeOH (10 mL) was added Pd/C (100 mg, 10% wet) atroom temperature. The resulting mixture was stirred under hydrogenballoon at room temperature for 16 hours; LC-MS showed that the reactionwas completed. Filtered off, the filtration was evaporated to dryness toafford the title product (410 mg, yield 87%) MS (ES+) C₂₂H₃₃NO₅requires: 391, found 392 [M+H]⁺.

Step 6: Synthesis of tert-butyl4-(4-hydroxyphenyl)-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl4-(4-(tert-butoxycarbonyloxy)phenyl)-4-methylpiperidine-1-carboxylate(410 mg, 1.0 mmol) in MeOH (5.0 mL) was added K₂CO₃ (691 mg, 5.0 mmol)at room temperature. The resulting mixture was stirred at roomtemperature at for 1 hour. LC-MS showed that the reaction was completed.The mixture was then extracted with EtOAc after water was added. Theorganic was washed with brine, dried over Na₂OS₄, and concentrated todryness to afford the title product (310 mg, quantitative) which wasused for the next step without further purification MS (ES+) C₁₇H₂₅NO₃requires: 291, found 236 [M+H-56]⁺.

Step 7: Synthesis of tert-butyl4-methyl-4-(4-(trifluoromethylsulfonyloxy)phenyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-hydroxyphenyl)-4-methylpiperidine-1-carboxylate (310 mg, 1.1 mmol)in DCM (15.0 mL) was added TEA (333 mg, 3.3 mmol) at room temperature.Tf₂O (372 mg, 1.3 mmol) in DCM (3 mL) was added at 0° C. dropwise during5 minutes. The resulting mixture was stirred at 0° C. for 4 hours; LC-MSshowed that the reaction was completed. The mixture was them extractedwith EtOAc after water was added. The organic was washed with brine,dried over Na₂SO₄ and concentrated to dryness to afford the titleproduct, which was used for the next step without further purification(270 mg, 8%) MS (ES+) C₁₈H₂₄F₃NO₅S requires: 423, found 424 [M+H]⁺.

Z. Synthesis of2-bromo-5-(4-methoxy-1-(oxetan-3-yl)piperidin-4-yl)pyridine Step 1:Synthesis of tert-butyl4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate

To a solution of 2-bromo-5-iodopyridine (11.3 g, 40 mmol) in 120 mL ofTHF was added nBuLi (17.6 ml, 2.5M in hexane) dropwise under N₂ at −78°C. The resulting solution was stirred at −78° C. for 2 h. Then asolution of tert-butyl 4-oxopiperidine-1-carboxylate (7.96 g, 40.0 mmol)in 20 ml of THF was added dropwise. The mixture was stirred at −78° C.for another 1 h. The reaction was quenched by addition of sat. NH₄Clsolution. After extracted with EtOAc, the organic phase was dried overNa₂SO₄ and concentrated. The residue was purified by silica gel column(PE/EtOAc=10:1) to afford the title product (8 g, yield 56%) as a yellowsolid. MS (ES+) C₁₅H₂₁BrN₂O₃ requires: 356, 358, found 357, 359 [M+H]⁺.

Step 2: Synthesis of tert-butyl4-(6-bromopyridin-3-yl)-4-methoxypiperidine-1-carboxylate

To a solution of tert-butyl4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (6.5 g, 18.1mmol) in 20 mL of DMF was added NaH (60%, 3.62 g, 90.5 mmol) at 0° C.The mixture was stirred at 0° C. for 30 min. Then MeI (7.7 g, 54.3 mmol)was added. The resulting mixture was stirred at RT overnight. Thereaction was quenched by addition of water carefully, and extracted withEtOAc. The organic phase was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to afford crude product which was used in the nextstep without purification. MS (ES+) C₁₆H₂₃BrN₂O₃ requires: 370, 372,found 315, 317 [M+H-56]⁺.

Step 3: Synthesis of 2-bromo-5-(4-methoxypiperidin-4-yl)pyridinehydrochloride

To a solution of tert-butyl4-(6-bromopyridin-3-yl)-4-methoxypiperidine-1-carboxylate (740 mg, 2mmol) in 5 mL of dioxane was added HCl (4 mL, 4M in dioxane). Theresulting mixture was stirred at RT for 4 h. The solvent was removed invacuo to afford crude product which was used in the next step withoutpurification. MS (ES+) C₁₁H₁₅BrN₂O requires: 270, 272, found 271, 273[M+H]⁺.

Step 4: Synthesis of2-bromo-5-(4-methoxy-1-(oxetan-3-yl)piperidin-4-yl)pyridine

To a solution of 2-bromo-5-(4-methoxypiperidin-4-yl)pyridinehydrochloride (400 mg, 1.30 mmol) and oxetan-3-one (468 mg, 6.50 mmol)in 10 mL of DCM and 10 mL of MeOH was added NaCNBH₃ (410 mg, 6.5 mmol)and drops of AcOH. The resulting solution was stirred at RT overnight.The reaction was quenched by addition of water and extracted with EtOAc.The organic phase was dried over Na₂SO₄ and concentrated in vacuo toafford crude product which was used in the next step withoutpurification. MS (ES+) C₁₄H₁₉BrN₂O₂ requires: 326, 328, found 327, 329[M+H]⁺.

AA. Synthesis of (S)-tert-butyl3-(6-bromopyridin-3-yl)-3-ethoxypiperidine-1-carboxylate and(R)-tert-butyl 3-(6-bromopyridin-3-yl)-3-ethoxypiperidine-1-carboxylateStep 1: Synthesis of tert-butyl3-(6-bromopyridin-3-yl)-3-hydroxypiperidine-1-carboxylate

To a solution of 2-bromo-5-iodopyridine (15 g, 52.8 mmol) in dry THF(300 mL) at −78° C. was added n-BuLi (2.5 M, 21 mL), and stirred at −78°C. for 1 hrs, followed by addition of tert-butyl3-oxopiperidine-1-carboxylate (10.5 g, 52.8 mmol) in THF. The reactionmixture was stirred at −78° C.˜−60° C. for 2 hrs, quenched by NH₄Cl/H₂Oand extracted by EA. The organic was dried to give a residue, which waspurified by flash chromatography to afford the title compound (8.4 g,45%). MS (ES+) C₁₅H₂₁BrN₂O₃ requires: 356, found: 357 [M+H]⁺.

Step 2: Synthesis of 6-bromo-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazine

To a solution of tert-butyl3-(6-bromopyridin-3-yl)-3-hydroxypiperidine-1-carboxylate (6.5 g, 18.1mmol) in DMF (150 mL) at 0° C. was added 60% NaH (3.00 g, 125 mmol), andstirred at 25° C. for 2 hrs, followed by addition of bromoethane (7.88g, 72.4 mmol). The mixture was stirred at 25° C. for another 5 hrs.Quenched by water and extracted with EA. Concentrated and purified byflash chromatography to give the title compound (5.7 g, 97%). MS (ES+)C₁₇H₂₅BrN₂O₃ requires: 385, found: 386[M+H]⁺.

Step 3: Chiral separation of6-bromo-4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazine

absolute configuration of P1 and P2 unknown.

The title compound (5.7 g) was separated by Chiral-HPLC (Chiralconditions: Co-Solvent: PA (0.1% DEA); Column: Cellulose-SC 4.6*100 mm 5um; Column Temperature:39.2; CO₂ Flow Rate: 3.6; Co-Solvent Flow Rate:0.4) to give P1 (1.8 g) and P2 (1.8 g).

BB. Synthesis of 3-(trimethylsilyloxy)oxetane-3-carbonitrile

To a mixture of oxetan-3-one (500 mg, 6.93 mmol) and triethylamine (1.39g, 13.8 mmol) in DCM (5 mL) was added trimethylsilanecarbonitrile (1.71g, 17.3 mmol). The mixture was stirred at RT for 16 h, then diluted withDCM, washed with saturated Na₂CO₃ solution and dried with Na₂SO₄anhydrous. The organic layer was separated and concentrated in vacuo toafford the title compound (800 mg, yield 67%) as a brown oil.

CC. Synthesis of 3-cyanooxetan-3-yl 1H-imidazole-1-carboxylate

To a mixture of 3-((trimethylsilyl)oxy)oxetane-3-carbonitrile (50 mg,291 μmol) in DCM (2 mL) was added CDI (51.8 mg, 320 μmol). The mixturewas stirred at rt for 4 hrs, which was added directly into the nextreaction solution. MS (ES+) C₈H₇N₃O₃ requires: 193, found: 194 [M+H]⁺.

DD. Synthesis of(3S,4S)-3-(4-bromophenyl)-4-(difluoromethoxy)-1-isopropylpiperidine

To a mixture of (3S,4S)-3-(4-bromophenyl)-1-isopropylpiperidin-4-ol (900mg, 3.01 mmol) and CuI (571 mg, 3.01 mmol) in dry CH₃CN (10 mL) wasdropwise added a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid(2.67 g, 15.00 mmol) in dry CH₃CN (5 mL) at 45° C. After that, thesolution was stirred at 45° C. for 2 hrs. The reaction was quenched withwater (1.0 mL) and extracted. The combined organic layers were washedwith water, dried over Na₂SO₄, filtered and concentrated. The residuewas purified by silica gel column chromatography (petroleum ether/ethylacetate/NH₃.MeOH=10/10/1) to afford the title compound (500 mg, 48%) asa yellow oil. MS (ES+) C₁₅H₂₀BrF₂NO requires: 347, 349, found: 348, 350[M+H]⁺.

Example 25. Synthesis of Other Exemplary Compounds

Table 1 indicates which Synthetic Protocol 1, 2, 3, or 4 described inthe disclosure was used to synthesize various compounds describedherein. Blank values indicate that a synthetic scheme other than one ofSynthetic Protocols 1-4 was used and that the synthetic scheme for suchcompound is set forth in the Examples.

TABLE 1 Synthetic Protocols used for Exemplary Compounds SyntheticCompound Scheme 100 2 101 2 102 2 103 1 104 1 105 2 106 2 107 2 108 2109 2 110 1 111 Ex. 18 112 1 113 2 114 1 115 4 116 2 117 1 118 1 119 2120 2 121 Ex. 19 122 2 123 2 124 2 125 2 126 2 127 1 128 2 129 2 130 1131 1 132 4 133 2 134 2 135 1 136 1 137 2 138 1 139 2 140 2 141 4 142 4143 2 144 2 145 2 146 2 147 2 148 1 149 1 150 4 151 2 152 1 153 1 154 1155 2 156 2 157 Ex. 16 158 2 159 2 160 2 161 1 162 1 163 1 164 2 165 2166 2 167 2 168 2 169 2 170 1 171 1 172 2 173 1 174 2 175 1 176 1 177 2178 2 179 2 180 2 181 2 182 4 183 2 184 1 185 1 186 1 187 2 188 2 189 2190 2 191 2 192 2 193 2 194 1 195 4 196 2 197 4 198 2 199 1 200 2 201 1202 2 203 1 204 1 205 3 206 2 207 2 208 4 209 2 210 2 211 2 212 1 213 1214 2 215 3 216 2 217 2 218 2 219 2 220 2 221 1 222 2 223 3 224 4 225 4226 3 227 3 228 2 229 1 230 3 231 2 232 4 233 2 234 3 235 2 236 2 237 4238 2 239 2 240 4 241 1 242 2 243 2 244 3 245 2 246 2 247 2 248 2 249 2250 3 251 4 252 2 253 2 254 2 255 2 256 2 257 2 258 2 259 1 260 Ex. 15261 1 262 1 263 1 264 1 265 2 266 2 267 2 268 2 269 2 270 2 271 2 272 1273 1 274 1 275 4 276 2 277 4 278 1 279 1 280 1 281 3 282 2 283 2 284 2285 2 286 4 287 2 288 2 289 2 290 2 291 3 292 1 293 3 294 3 295 2 296 1297 2 298 4 299 4 300 4 301 3 302 3 303 1 304 1 305 2 306 1 307 2 308 1309 1 310 1 311 4 312 2 313 2 314 1 315 2 316 2 317 4 318 1 319 1 320 2321 1 322 2 323 2 324 4 325 2 326 2 327 1 328 4 329 1 330 1 331 1 332 3333 2 334 1 335 1 336 3 337 4 338 4 339 2 340 4 341 4 342 4 343 2 344 1345 2 346 4 347 4 348 4 349 2 350 1 351 2 352 2 353 4 354 2 355 1 356 4357 2 358 4 359 1 360 2 361 3 362 2 363 1 364 4 365 4 366 4 367 1 368 3369 4 370 4 371 2 372 4 373 2 374 2 375 2 376 1 377 4 378 2 379 4 380 4381 4 382 4 383 4 384 4 385 4 386 4 387 4 388 2 389 2 390 1 391 2 392 4393 4 394 4 395 4 396 4 397 2 398 4 399 2 400 2 401 4 402 1 403 Ex. 17404 4 405 4 406 4 407 2 408 4 409 4 410 4 411 4 412 4 413 4 414 4 415 4416 4 417 2 418 2 419 1 420 4 421 4 422 3 423 4 424 4 425 2 426 4 427 1428 4 429 3 430 4 431 4 432 4 433 3 434 4 435 4 436 2 437 2 438 1 439 3440 3 441 4 442 4 443 1 444 4 445 4 446 4 447 3 448 4 449 2 450 2 451 2452 5 453 2 454 2 455 2 456 2 457 2 458 2 459 1 460 1 461 2 462 2 463 2464 2 465 5 466 5 467 5 468 2 469 2 470 2 471 2 472 2 473 2 474 2 475 2476 5 477 5 478 2 479 2 480 2 481 2 482 2 483 2 484 2 485 2 486 2 487 2488 2 489 2 490 2 491 2 492 2 493 2 494 2 495 2 496 2 497 2 498 2 499 5500 2 501 2 502 2 503 2 504 2 505 2 506 2 507 2 508 2 509 4 510 4 511 4512 2 513 2 514 4 515 2 516 2 517 2 518 2 519 2 520 2 521 2 522 1 523 1524 2 525 4 526 4 527 4 528 2 529 4 530 4 531 2 532 4 533 2 534 4 535 4536 4 537 2 538 2 539 2 540 2 541 2 542 2 543 2 544 2 545 2 546 2 547 4548 2 549 2 550 4 551 4 552 4 553 2 554 4 555 2 556 2 557 2 558 2 559 2560 2 561 2 562 2 563 2 564 2 565 2 566 2 567 2 568 2 569 2 570 2 571 5572 4 573 4 574 4 575 2 576 2 577 2 578 2 579 4 580 4 581 5 582 5 583 2584 5 585 2 586 2 587 2 588 2 589 2 590 4 591 2 592 2 593 2 594 2 595 4596 4 597 2 598 2 599 2 600 2 601 2 602 5 603 4 604 4 605 2 606 2 607 4608 4 609 2 610 2 611 2 612 5 613 2 614 2 615 2 616 2 617 4 618 4 619 2620 2 621 4 622 2 623 4 624 2 625 2 626 2 627 4 628 2 629 4 630 2 631 2632 4 633 2 634 2 635 2 636 2 637 4 638 4 639 2 640 2 641 2 642 2 643 2644 2 645 2 646 2 647 2 648 5 649 5 650 5 651 2 652 4 653 2 654 2 655 2656 2 657 2 658 2 659 2 660 2 661 4 662 2 663 4 664 4 665 3 666 4 667 4668 2 669 2 670 4 671 2 672 2 673 2 674 2 675 2 676 4 677 4 678 2 679 2680 2 681 4 682 2 683 2 684 2 685 2 686 2 687 2 688 2 689 2 690 2 691 2692 2 693 2 694 5 695 2 696 2 697 2 698 2 699 2 700 2 701 5 702 4 703 4704 4 705 4 706 2 707 2 708 4 709 4 710 2 711 2 712 2 713 2 714 2 715 2716 2 717 2 718 2 719 2 720 2 721 2 722 2 723 2 724 2 725 2 726 2 727 2728 4 729 2 730 2 731 2 732 2 733 2 734 2 735 2 736 2 737 5 738 2 739 2740 2 741 2 742 4 743 2 744 2 745 2 746 2 747 2 748 2 749 2 750 2 751 2752 2 753 2 754 2 755 2 756 2 757 2 758 2 759 2 760 2 761 2 762 2 763 2764 2 765 2 766 2 767 2 768 2 769 2 770 2 771 2 772 2 773 2 774 2 775 2776 2 777 2 778 2 779 2 780 2 781 2 782 2 783 2 784 2 785 2 786 2 787 2788 2 789 3 790 3 791 2 792 2 793 3 794 3 795 3 796 2 797 2 798 2 799 2800 2 801 2 802 2 803 3 804 2 805 2 806 2 807 2 808 2 809 3 810 3 811 2812 3 813 2 814 3 815 2 816 2 817 2 818 2 819 2 820 2 821 2 822 3 823 2824 2 825 3 826 3 827 3 828 3 829 3 830 2 831 2 832 3 833 2 834 2 835 2836 3 837 3 838 3 839 2 840 3 841 3 842 3 843 2 844 2 845 2 846 2 847 3848 2 849 2 850 2 851 3 852 2 853 3 854 3 855 2 856 2 857 2 858 2 859 2860 2 861 2 862 2 863 2 864 3 865 3 866 3 867 3 868 2 869 2 870 3 871 3872 3 873 2 874 2 875 2 876 3 877 3 878 3 879 3 880 2 881 2 882 2 883 2884 2 885 2 886 2 887 2 888 2 889 2 890 3 891 2 892 2 893 2 894 2 895 2896 2 897 2 898 2 899 2

Example 26. ALK Binding Assays

Binding assays were conducted using the LANTHASCREEN® technology(ThermoFisher Scientific). LANTHASCREEN® is a competitive binding,displacement assay where the assumed steady state occupancy of thebinding site is measured using a time-resolved, fluorescence energytransfer (TR-FRET) readout between a fluorescent tracer and Europium(Eu)-tagged antibody specific for the kinase or expression tag (e.g.GST) of interest. Displacement of the tracer by a compound of thedisclosure reduces, and is directly proportional to, the TR-FRET betweenthe tracer and the antibody. Tracer was used at a concentration equal toor near to its K_(d) for the kinase. The Eu-tagged antibody wastypically used in excess to ensure sampling of all competent proteincapable of binding the tracer.

For these assays a mutant ALK2 was used that was N-terminally taggedwith GST (ALK2 R206H Carna Bioscience (09-148) or ALK2 R206HThermoFisher (PV6232)); a Eu-tagged anti-GST antibody (ThermoFisher) andKinase Tracer 178 (ThermoFisher). In all cases, the kinase (2-5 nM) wasmixed with Eu-tagged antibody (10 nM) mix and tracer (50 nM) wereincubated with test compound titrations prepared in 100% DMSO (1% DMSOfinal) for 30 minutes at room temperature. All reagents and compoundswere dissolved in Kinase Buffer A (ThermoFisher) to achieve the finalconcentration. The plates were read on a PerkinElmer EnVision®multilabel plate reader or a BioTek Synergy Neo plate reader, and theassay signal was represented as a ratio of the TR-FRET emission (λ_(ex)330 nm, λ^(em) 662 nm and λ^(em) 665 nm). This readout was normalized to0% and 100% inhibited control wells, plotted against inhibitorconcentration, and fitted to a 4-parameter log dose response curve.

The results of this assay are shown in Table 2 in the column labelled“Binding Assay” wherein “A” represents an IC₅₀ of less than or equal to10 nM; “B” represents an IC₅₀ of greater than 10 nM and less than orequal to 50 nM; and “C” represents an IC₅₀ of greater than 50 nM. Blankvalues in the table indicate that the particular compound was not testedin this assay.

Example 27. Cell-Based ALK2-R206H Cell Activity Assay A. Cell LineHEK293-ALK2-R206H

A HEK293 (ATCC, Cat^(#) CRL1573) based stable cell line expressing humanALK2 R206H cDNA (synthesized by GeneScript, Piscataway, N.J.) and a FLAGtag at the C-terminus was generated by lentivirus transduction andsubsequent blasticidin (Life Technologies, Cat^(#)-A1113902) selectionat 10 gg/ml for >2 wks. This cell line was named HEK293-ALK2-R206H.

B. Measurement of Smad1-Ser463/Ser465 Phosphorylation by AlphaLISA

HEK293-ALK2-R206H cells were grown, harvested and then resuspended inserum-free, phenol red-free DMEM high glucose media (Life Technologies,Cat^(#)-31053). The media also contained 50 units/ml penicillin and 50μg/ml streptomycin (Life Technologies, Cat^(#-)15070-063).HEK293-ALK2-R206H cells were then plated in white opaque 384-wellsmicroplates (2×10⁴/well) (OptiPlate-384, PerkinElmer, Waltham, Mass.,Cat^(#)6007299) overnight (>16 h) at 370 C, 5% CO₂ for use in the assay.

Test compounds were first diluted to 4 mM or 0.4 mM and then seriallydiluted 3-fold into 10 different concentrations using DMSO. Eachconcentration of compound was further diluted 40-fold with phenolred-free DMEM (Life Technologies, Cat#-31053). Two μl of the dilutedcompounds were then dispensed into the HEK293-ALK2-R206H cell-containingwells of the microplates in duplicates. In this way, each compound wastested in 10 doses (3-fold serial dilution with the top concentrationbeing 10 μM or 1 μM). Liquid handling was achieved using a BravoAutomated Liquid Handling Platform (Agilent Technologies). DMSO withoutcompound was used as a negative control. The positive control was 1 μMLDN193189, a known bone morphogenetic protein (BMP inhibitor).

After 2-3 hours of incubation with test compound or control, the cellswere lysed and signal was developed using ALPHASCREEN® SUREFIRE® SMAD1(p-Ser463/465) cellular kinase assay kit (PerkinElmer, Cat^(#) TGRSM1S10K) following the manufacturer's recommended protocol. Themicroplates were read using Perkin Elmer ENVISION® plate reader(emission 520-620 nM). The signal reflected the level ofphospho-Ser/463/465-Smad1 in the lysate. The raw data were plotted usingthe DMSO negative and LDN193189 positive controls as the 0% and 100%inhibition, respectively. The 10-point dose response curve was used tocalculate the IC50 values.

The results of this assay are shown in Table 2 in the column labelled“Cell Assay” wherein “A” represents an IC₅₀ of less than or equal to 100nM; “B” an IC₅₀ of greater than 100 nM and less than or equal to 500 nM;“C” an IC₅₀ of greater than 500 nM. Blank values in the table indicatethat the particular compound was not tested in this assay.

In Table 2, the following designations are used:

For “Binding Assay” data: ≦10 nM=A; ≧10-50 nM=B; >50 nM=C; and a blankvalue in the table indicates that the particular compound was not testedin this assay.

For “Cell Line” data: ≦100 nM=A; ≧100-500 nM=B; >500 nM=C; and a blankvalue in the table indicates that the particular compound was not testedin this assay.

TABLE 2 ALK2 Inhibitory Activity of Exemplary Compounds of theDisclosure Binding Cell Compound Assay Line 100 A B 101 C 102 A B 103 BC 104 A B 105 B 106 C 107 A A 108 B 109 A A 110 B B 111 A B 112 A B 113A A 114 A C 115 A B 116 A A 117 A B 118 A B 119 C 120 A B 121 A 122 A A123 A B 124 A A 125 A A 126 B 127 A A 128 B B 129 A A 130 A B 131 A B132 A A 133 A A 134 A B 135 B B 136 B 137 A A 138 B 139 A 140 A A 141 B142 A B 143 A A 144 A B 145 A A 146 A B 147 A A 148 A A 149 A A 150 A A151 C 152 A A 153 A B 154 A B 155 A B 156 A A 157 C 158 A B 159 A A 160A B 161 A A 162 A A 163 A A 164 A B 165 B 166 A 167 A A 168 B 169 A B170 B B 171 B 172 A B 173 B C 174 A B 175 B 176 B 177 A A 178 A A 179 AA 180 A A 181 A A 182 A A 183 B 184 A A 185 A A 186 A B 187 A A 188 A A189 A A 190 A 191 A A 192 A A 193 A A 194 B B 195 A A 196 A B 197 B B198 A 199 A A 200 A A 201 A A 202 A A 203 A A 204 A A 205 B B 206 A 207A A 208 A A 209 A A 210 A A 211 A A 212 A B 213 A A 214 B B 215 B 216 AA 217 A B 218 B 219 A A 220 A 221 A B 222 A A 223 B B 224 A A 225 A A226 A A 227 A A 228 A A 229 A A 230 A A 231 A A 232 A B 233 B B 234 A A235 A B 236 A B 237 A A 238 A B 239 A 240 A A 241 A A 242 A B 243 A A244 A 245 B B 246 A A 247 A A 248 A A 249 A A 250 A A 251 A A 252 A B253 A B 254 A A 255 A B 256 A B 257 A A 258 A A 259 B C 260 A B 261 A A262 A B 263 A B 264 A B 265 A A 266 A A 267 A A 268 B B 269 A A 270 A A271 A B 272 B B 273 B 274 A B 275 A A 276 A A 277 A A 278 A A 279 B B280 B B 281 A A 282 A A 283 A B 284 A A 285 A A 286 A B 287 A A 288 A A289 A A 290 A A 291 B 292 A A 293 A A 294 B 295 A A 296 A B 297 A A 298A A 299 A A 300 A A 301 A B 302 A A 303 A A 304 A A 305 A A 306 B 307 AB 308 A A 309 A B 310 A B 311 C 312 A A 313 A A 314 B C 315 B B 316 A B317 A B 318 A B 319 C 320 A A 321 A A 322 A A 323 A A 324 A A 325 A A326 A A 327 B B 328 A B 329 A B 330 A B 331 B 332 A A 333 A A 334 B B335 C C 336 A A 337 A A 338 A B 339 A A 340 A A 341 A A 342 B 343 A B344 B B 345 A A 348 A A 349 A A 350 A A 351 A A 352 A B 353 A B 354 A A355 B C 356 B 357 A A 359 A C 360 A B 361 A B 362 B 363 A B 364 A A 365A A 366 A A 367 A A 368 A A 369 A A 370 A A 371 A A 372 A 373 B C 374 B375 A A 376 A A 377 A B 378 A 379 A B 380 A A 381 A A 382 A A 383 A A384 A A 385 A A 386 A B 387 A A 388 A A 390 B B 391 A A 392 B 393 A B397 B 399 A A 400 A A 401 A B 402 A B 403 C 404 A B 405 A 406 A A 407 AA 408 A A 409 A A 410 C 411 A B 412 A A 413 A A 414 B 415 A A 417 B 418A A 419 A A 420 A A 421 A A 422 A A 423 A B 425 C 426 A A 427 A B 428 AB 429 A A 430 A A 431 A B 432 A A 433 C 434 A A 435 A A 436 A A 437 A A438 B 439 B 440 C 441 A A 442 A A 443 B 444 B 445 A A 446 A 447 B C 448A B 449 A 450 A B 451 A A 452 A A 453 A A 454 A B 455 A A 456 A B 457 AB 458 A 459 A A 460 A A 461 A 462 A B 463 A A 464 A A 465 A B 466 A A467 A B 468 A A 469 A A 470 A A 471 C 472 A 473 A A 474 A B 475 A A 476A A 477 A A 478 A A 479 A A 480 A A 481 A A 482 A A 483 A A 484 A A 485A A 486 A A 487 A A 488 A A 489 A A 490 A A 491 A A 492 A A 493 A A 494A A 495 A A 496 A A 497 A A 498 A A 499 A B 500 A B 501 A B 502 A A 503A B 504 A B 505 A A 506 B 507 A A 508 A B 509 A A 510 A A 511 A A 512 AA 513 A A 514 A A 515 A A 516 A A 517 A A 518 A A 519 A A 520 A A 521 AA 522 A A 523 A A 524 A A 525 A 526 A A 527 A A 528 B 529 A 530 A A 531A A 532 A A 533 A A 534 A A 535 A 536 A 537 A A 538 A A 539 A A 540 A A541 A A 542 A A 543 A A 544 A A 545 A A 546 A A 547 A 548 A C 549 A A550 A A 551 A A 552 A 553 B 554 A B 555 A 556 A A 557 A A 558 A A 559 AA 560 A A 561 A A 562 A A 563 A A 564 A A 565 A A 566 A A 567 A A 568 AA 569 A 570 A A 571 A 572 A A 573 A A 574 A 575 A B 576 A A 577 A A 578A A 579 A A 580 A A 581 A A 582 A A 583 A A 584 A 585 A A 586 A B 587 AA 588 A A 589 A A 590 A 591 A A 592 A A 593 A A 594 A A 595 A A 596 A B597 A A 598 A A 599 A A 600 A A 601 A A 602 A 603 A A 604 A A 605 A A606 A A 607 A 608 A B 609 A A 610 A A 611 A A 612 A 613 A A 614 A A 615A A 616 A A 617 A B 618 A A 619 A A 620 A A 621 A B 622 A C 623 A B 624A A 625 A A 626 A A 627 A A 628 A A 629 A A 630 A A 631 A A 632 A B 633A A 634 A A 635 A A 636 A A 637 A A 638 A A 639 A 640 A 641 A A 642 A A643 A A 644 A A 645 A A 646 A A 647 A A 648 A A 649 A A 650 A A 651 A A652 A A 653 A A 654 A A 655 A A 656 A A 657 A A 658 A A 659 A A 660 A A661 A B 662 A A 663 A A 664 A B 665 A A 666 A A 667 A A 668 A B 669 A A670 A 671 A A 672 A A 673 A A 674 A A 675 A A 676 A A 677 A A 678 A A679 A A 680 A A 681 A A 682 A A 683 A A 684 A A 685 A A 686 A A 687 A A688 A A 689 A B 690 A A 691 A A 692 A A 693 A A 694 A A 695 A A 696 A A697 A A 698 A A 699 A A 700 A 701 A A 702 A A 703 A A 704 A A 705 A A706 A A 707 A 708 A A 709 A B 710 A A 711 A A 712 A A 713 A A 714 A A715 A A 716 A A 717 A 718 A A 719 A A 720 A A 721 A A 722 A A 723 A A724 A A 725 A A 726 A B 727 A A 728 A A 729 A A 730 A 731 A A 732 A B733 A A 734 A A 735 A A 736 A A 737 A A 738 A A 739 A A 740 A A 741 A A742 A 743 A A 744 A A 745 A A 746 A A 747 A A 748 A A 749 A A 750 A A751 A 752 A B 753 A A 754 A A 755 A B 756 A 757 A 758 A 759 A 760 A B761 A A 762 A B 763 A A 764 A A 765 A 766 A B 767 A 768 A A 769 A 770 AA 771 A A 772 A 773 A B 774 A A 775 A A 776 A A 777 A A 778 A A 779 A A780 A A 781 B 782 A A 783 A A 784 A A 785 A B 786 A A 787 A A 788 A A789 A C 790 A C 791 A A 792 A A 793 A A 794 A A 795 A A 796 A A 797 A A798 A A 799 A A 800 A A 801 A A 802 A A 803 A 804 A A 805 A A 806 A 807A 808 A A 809 A A 810 A A 811 A A 812 A B 813 A A 814 A A 815 A A 816 AA 817 A A 818 A A 819 A A 820 A A 821 A A 822 B 823 A A 824 A A 825 A B826 A A 827 A B 828 A B 829 A A 830 A B 831 A A 832 A A 833 A A 834 A A835 A A 836 A B 837 A B 838 A B 839 A A 840 A B 841 B 842 B 843 A A 844A A 845 A A 846 A A 847 A C 848 A A 849 A A 850 A A 851 A B 852 A A 853A B 854 A A 855 A A 856 A A 857 A A 858 A A 859 A A 860 A A 861 A A 862A 863 A A 864 A A 865 A A 866 A 867 A A 868 A A 869 A A 870 A A 871 A A872 A A 873 A A 874 A B 875 A A 876 A A 877 A A 878 A A 879 A A 880 A A881 A 882 A A 883 A A 884 A A 885 A A 886 A A 887 A A 888 A A 889 A A890 A A 891 A A 892 A A 893 A A 894 A A 895 A B 896 A A 897 A A 898 A A899 A A

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference.

EQUIVALENTS

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The disclosure includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Thedisclosure includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the disclosure encompasses all variations, combinations,and permutations in which one or more limitations, elements, clauses,and descriptive terms from one or more of the listed claims areintroduced into another claim. For example, any claim that is dependenton another claim can be modified to include one or more limitationsfound in any other claim that is dependent on the same base claim. Whereelements are presented as lists, e.g., in Markush group format, eachsubgroup of the elements is also disclosed, and any element(s) can beremoved from the group. It should it be understood that, in general,where the disclosure, or aspects of the disclosure, is/are referred toas comprising particular elements and/or features, certain embodimentsof the disclosure or aspects of the disclosure consist, or consistessentially of, such elements and/or features. For purposes ofsimplicity, those embodiments have not been specifically set forth inhaec verba herein. Where ranges are given, endpoints are included.Furthermore, unless otherwise indicated or otherwise evident from thecontext and understanding of one of ordinary skill in the art, valuesthat are expressed as ranges can assume any specific value or sub-rangewithin the stated ranges in different embodiments of the disclosure, tothe tenth of the unit of the lower limit of the range, unless thecontext clearly dictates otherwise.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the disclosure described and claimed herein. Suchequivalents are intended to be encompassed by the following claims.

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: ring A is phenylor heteroaryl, wherein ring A is substituted with 0, 1, 2, or 3independently selected substituents in addition to R²; R¹ is selectedfrom NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, —O—C₁-C₆ alkyl,—C(O)—C₁-C₄ alkyl, carbocyclyl, heterocyclyl, —O—(C₀-C₄alkylene)-carbocyclyl, —O—(C₀-C₄ alkylene)-heterocyclyl, —NH—(C₀-C₄alkylene)-carbocyclyl, —NH-aryl, —NH—O—(C₁-C₄ alkyl), —S— heterocyclyl,and —NH—(C₀-C₄ alkylene)-heterocyclyl, wherein each alkyl, alkylene,carbocyclyl, and heterocyclyl portion of R¹ is unsubstituted, or isindependently substituted with 1, 2, 3, or 4 independently selectedsubstituents; or R¹ is taken together with one R³ to form a saturatedring fused to the piperazine ring in formula (I), and wherein the ringformed by R¹ and R³ is unsubstituted, or is substituted with 1, 2, or 3independently selected substituents; R² is selected from halo, C₁-C₆alkyl, heterocyclyl, cycloalkyl, —NH—(C₀-C₄ alkylene)-heterocyclyl,—(C₁-C₄ alkylene)-heterocyclyl, —(C₁-C₄ alkylene)-NH-heterocyclyl, and—O—(C₀-C₄ alkylene)-heterocyclyl, wherein any heterocyclyl, cycloalkyl,alkyl or alkylene portion of R² is unsubstituted, or is substituted with1, 2, 3, or 4 independently selected substituents; or R² is takentogether with any ring atom in ring A to form a cycloalkyl or saturatedheterocyclyl ring that is fused, spirofused, or bridged to ring A, andwherein the ring formed by R² and the ring atom in ring A isunsubstituted, or is substituted with 1, 2, or 3 independently selectedsubstituents; each R³, if present, is independently selected from C₁-C₄alkyl and C₁-C₄ haloalkyl; and n is 0, 1, 2, or
 3. 2. The compound ofclaim 1, wherein n is 0 or 1; and R³, if present, is selected frommethyl, ethyl, and —CHF₂.


3. The compound of claim 1, wherein ring A is selected from: wherein:“1” represents a portion of ring A bound to a pyrrolo[1,2-b]pyridazinemoiety; “2” represents a portion of ring A bound to R²; and ring A issubstituted with 0, 1, 2, or 3 independently selected substituents inaddition to R².
 4. The compound of claim 3, wherein ring A is selectedfrom


5. The compound of claim 1, wherein ring A is substituted with 0, 1, or2 substituents in addition to R², wherein each of the substituents isindependently selected from —CN, halo, methyl, and —OCHF₂.
 6. Thecompound of claim 1, wherein R¹ is selected from —C(O)—(C₁-C₃ alkyl),C₁-C₃ alkyl, —O—(C₁-C₅ alkyl), —NH(C₁-C₅ alkyl), —N(C₁-C₄ alkyl)₂,—NH—(C₃-C₆ cycloalkyl), C₃-C₆ cycloalkyl, —O—(C₃-C₆ cycloalkyl),—O—(C₁-C₃ alkyl)-(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)-(C₃-C₆cycloalkyl), —O—(C₀-C₃ alkylene)-(O-containing heterocyclyl), —NH—(C₀-C₃alkylene)-(O-containing heterocyclyl), an O-containing heterocyclyl, anN-containing heterocyclyl, —O—(C₀-C₃ alkylene)-(N-containingheterocyclyl), —S—(C₀-C₃ alkylene)-(O-containing heterocyclyl),—NH—O—(C₁-C₃ alkyl), and —NH-phenyl, wherein any alkyl, cycloalkyl,phenyl, or heterocyclyl portion of R¹ is unsubstituted, or issubstituted with 1, 2, or 3 substituents independently selected fromdeuterium, halo, cyano, acetyl, C₁-C₄ alkyl, C₁-C₄ haloalkyl, —O—C₁-C₄alkyl, —C₁-C₄ alkylene-O—C₁-C₄ alkyl, optionally substituted heteroaryl,optionally substituted phenyl, optionally substituted cycloalkyl, —COOH,and —OH; or R¹ is taken together with any ring atom in the piperazinemoiety of formula (I) to form a carbocyclyl or heterocyclyl ring fusedto the piperazine moiety.
 7. The compound of claim 1, wherein R² isselected from halo, cycloalkyl, heterocyclyl, —O—(C₀-C₄alkylene)-(heterocyclyl), —(C₁-C₃ alkylene)-heterocyclyl, —(C₁-C₃alkylene)-NH—(C₁-C₃ alkyl), -(hydroxy-substituted C1-C₃alkylene)-NH—(C₁-C₃ alkyl), C1-C₄ alkyl substituted with both hydroxyand one or more of amino, C₁-C₄ alkylamino or di-C₁-C₄ alkylaminocyano-substituted C₁-C₄ alkyl, —OH, —S(O)₂—C₁-C₄ alkyl, and -(aminosubstituted C₁-C₃ alkylene)-heterocyclyl, or R² is taken together with aring atom in ring A to form a heterocyclyl or a carbocyclyl that isfused to ring A, wherein any heterocyclyl, cycloalkyl, or carbocyclyl isoptionally substituted with up to 3 substituents independently selectedfrom halo, cyano, —OH, —NH₂, —NH(C₁-C₄ alkyl), —NH—C(O)—O—(C₁-C₄ alkyl),═O, —OH, —C(O)—C₁-C₄ alkyl, —C₁-C₄ alkyl, deuterated C₁-C₄ alkyl, —C₁-C₄haloalkyl, hydroxy-substituted —C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —O—C₁-C₄haloalkyl, —(C₁-C₄ alkylene)-O—(C₁-C₄ alkyl), -(amino substituted C₁-C₄alkylene)-O—(C₁-C₄ alkyl), —(C₁-C₄ alkylene)-O—(C₁-C₄ haloalkyl),—C(O)—O—C₁—C₄ alkyl, —COOH, C₃-C₆ cycloalkyl, an optionally substitutedsecond heterocyclyl, and —NH-(optionally substituted secondheterocyclyl).
 8. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein: X is C(R¹³) orN; R¹¹ is selected from —NH—(C₃-C₄ cycloalkyl); —NH—C₁-C₃ alkyl;—O—C₃-C₄ cycloalkyl; —O—C₁-C₃ alkyl optionally substituted with one ormore substituents selected from fluoro, hydroxy, —CN, and deuterium; and—O—(O-containing heterocycle); R¹² is selected from piperidin-3-yloptionally 3-substituted with C₁-C₃ alkoxy, fluoro, C₁-C₃ alkyl, or —CN;and piperidin-4-yl optionally 4-substituted with C₁-C₃ alkoxy, fluoro,C1-C₃ alkyl, —CN, wherein R¹² is additionally optionally 1-substitutedwith C₁-C₅ alkyl optionally substituted with one or more —OH and/or oneor more —NH₂; R¹³ is selected from hydrogen, —CN and fluoro; and R¹⁴, ifpresent, is fluoro.
 9. The compound of claim 8, wherein the compound isa compound of formula IIa:

or a pharmaceutically acceptable salt thereof, wherein: X, R¹¹, R¹⁴, andsubvariables thereof are as defined in claim 10; R¹⁵ is selected fromhydrogen, C₁-C₃ alkoxy, fluoro, C₁-C₃ alkyl, and —CN; and R¹⁶ ishydrogen or C₁-C₅ alkyl optionally substituted with one or more —OHand/or one or more —NH₂.
 10. The compound of claim 8, wherein thecompound is a compound of formula IIb:

or a pharmaceutically acceptable salt thereof, wherein: X, R¹¹, R¹⁴, andsubvariables thereof are as defined in claim 10; R¹⁵ is selected fromhydrogen, C₁-C₃ alkoxy, fluoro, C₁-C₃ alkyl, and —CN; and R¹⁶ ishydrogen or C₁-C₅ alkyl optionally substituted with one or more —OHand/or one or more —NH₂.
 11. The compound of claim 10, wherein thecompound is a compound of formula IIb-1:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim10, wherein the compound is a compound of formula IIb-2:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim8, wherein R¹⁴ is absent.
 14. The compound of claim 8, wherein R¹³ ishydrogen.
 15. The compound of claim 8, wherein R¹¹ is selected from—NH—C₁-C₃ alkyl; —O—C₁-C₃ alkyl optionally substituted with one or moresubstituents selected from fluoro, hydroxy, —CN, and deuterium;oxetan-3-yloxy and tetrahydrofuran-3-yl.
 16. A compound selected fromany one of the compounds of 100-899 in Table
 1. 17. A pharmaceuticalcomposition, comprising at least one compound of claim 1, and at leastone pharmaceutically acceptable excipient.
 18. A method of treating orameliorating fibrodysplasia ossificans progressiva in a subject,comprising administering to the subject in need thereof apharmaceutically effective amount of at least one compound of claim 1 ora pharmaceutical or a pharmaceutically acceptable salt thereof.
 19. Themethod of claim 18, wherein the subject has a mutation in an ALK2 genethat results in the expression of an ALK2 enzyme having an amino acidmodification selected from one or more of L196P, PF197-8L, R202I, R206H,Q207E, R258S, R258G, G328A, G328W, G328E, G328R, G356D, and R375P. 20.The method of claim 18, wherein the ALK2 enzyme has the amino acidmodification R206H.